Stimulation design for neuromodulation

ABSTRACT

The present application relates to a new stimulation design which can be utilized to treat neurological conditions. The stimulation system produces a burst mode stimulation which alters the neuronal activity of the predetermined site, thereby treating the neurological condition or disorder. The burst stimulus comprises a plurality of groups of spike pulses having a maximum inter-spike interval of 100 milliseconds. The burst stimulus is separated by a substantially quiescent period of time between the plurality of groups of spike pulses. This inter-group interval may comprise a minimum of 5 seconds.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/846,663, filed Mar. 18, 2013 (now U.S. Pat. No. 8,897,870), which isa continuation of U.S. patent application Ser. No. 13/314,966, filedDec. 8, 2011 (now U.S. Pat. No. 8,401,655), which is continuation ofU.S. patent application Ser. No. 12/790,505, filed May 28, 2010 (nowabandoned), which is a continuation of U.S. patent application Ser. No.11/254,465, filed Oct. 20, 2005 (now U.S. Pat. No. 7,734,340), whichclaims the benefit of U.S. Provisional Application No. 60/620,781, filedOct. 21, 2004, the disclosures of which are incorporated herein byreference in their entirety.

TECHNICAL FIELD

The present application relates to a new stimulation system and methodwhich can be utilized to treat neurological conditions and/or disorders.

BACKGROUND OF THE INVENTION

Different firing modes or frequencies occur in the brain and/or otherneuronal tissue, for example tonic firing and burst firing (irregular orregular burst firing). Such firing modes can be utilized for normalprocessing of information, however, alteration of the firing modes, mayalso lead to pathology.

For example, certain neurological conditions are associated withhyperactivity of the brain and can be traced to a rhythmic burst firingor high frequency tonic firing (e.g., tinnitus, pain, and epilepsy).Other conditions can be associated with an arrhythmic burst firing or adesynchronized form of tonic and burst firing (e.g., movement disordersand hallucinations).

During the past decade, neuromodulation systems have been used tomodulate various areas of the brain, spinal cord, or peripheral nerves(See, for example, U.S. Pat. Nos. 6,671,555; 6,690,974). These types ofsystems utilize tonic forms of electrical stimulation. The disadvantageto these systems is that the neurological condition is related to a highfrequency tonic rhythm or bursting type rhythm, it may be difficult fora second tonic stimulation to alter the diseased stimulation to actuallyresult in treatment.

Thus, the present invention is the first to describe a neuromodulationdesign or stimulation parameters in which the stimulation parametersproduce burst stimulation to override or alter the pathological and/orphysiological stimulation to treat a neurological condition.

BRIEF SUMMARY OF THE INVENTION

The present invention is directed to a method and/or system ofstimulating nerve tissue of a patient using an implantable pulsegenerator. The method comprises generating, by the implantable pulsegenerator, a burst stimulus that comprises a plurality of groups ofspike pulses, wherein the burst stimulus is substantially quiescentbetween the plurality of groups, wherein each spike within each group isseparated by a maximum inter-spike interval and each group of spikes isseparated by a minimum inter-group interval, wherein the maximuminter-spike interval is 100 milliseconds and the minimum inter-groupinterval is 5 seconds; providing the burst stimulus from the implantablepulse generator to a medical lead; and applying the burst stimulus tonerve tissue of the patient via one or several electrodes of the medicallead. More particularly, each spike in each group occurs from a plateaupotential, which is controllable by a parameter stored in theimplantable pulse generator.

In certain embodiments, the method of stimulating nerve tissue comprisescontrolling a number of spikes within a group of spikes of the burststimulus according to a parameter stored in the implantable pulsegenerator. The pulse generator is also capable of controlling a spikeamplitude according to a parameter stored in the implantable pulsegenerator. In certain embodiments, the method comprises an amplitude ofthe hyperpolarizing pulse is controllable by a parameter stored in theimplantable pulse generator.

Yet further, the method of stimulating nerve tissue comprisescontrolling an inter-spike interval according to a parameter stored inthe implantable pulse generator and/or controlling an inter-groupinterval according to a parameter stored in the implantable pulsegenerator and/or controlling a number of groups within the burststimulus according to a parameter stored in the implantable pulsegenerator.

In another embodiment, the method further comprises detecting, by theimplantable pulse generator, hyperactivity within neural tissue using asensor in the implantable pulse generator, wherein the generating theburst stimulus occurs in response to the detecting. The sensor iscoupled to one or several electrodes of the medical lead.

The present invention is directed to a method and a system ofneuromodulation by providing a burst mode stimulus to either central orperipheral neuronal tissue in which the burst mode stimulus alters theactivity of the neuronal tissue. It is envisioned that this method ofneuromodulation can be used to treat various neurological disorders orneurologically mediated disorders. Stimulation can be in the form ofelectrical and/or chemical stimulation. In certain embodiments, theinvention uses electrical stimulation and/or chemical stimulation (e.g.,one or more pharmaceuticals) to treat the neurological condition. Inaddition to electrical and/or chemical stimulation, magnetic stimulationand/or thermal as well as sound stimulation can also be used. Magneticstimulation can be provided by internally implanted probes or byexternally applied directed magnetic fields. Thermal stimulation can beprovided by using implanted probes that are regulated to produce or emitheat and/or cold temperatures.

In certain embodiments, the present invention comprises a therapeuticstimulation system for treating neurological conditions or disordershaving a surgically implanted device in communication with apredetermined site, which can be either a central neuronal or peripheralneuronal tissue site. The device can include an electrode, for examplean electrode assembly or electrical stimulation lead. The electrode iscoupled to a signal source (e.g., an electrical signal source), which,in turn, is operated to stimulate the predetermined site.

In certain embodiments, it is envisioned that the present inventioncomprises a method of treating a neurological disorder comprising thestep of providing an electrical burst stimulus to a predeterminedneuronal tissue site whereby the stimulus alters neuronal activitythereby treating the disorder.

The burst stimulus comprises a frequency in the range of about 1 Hz toabout 300 Hz, more particular, in the range of about 1 Hz to about 18Hz, and more particularly, in the range of about 1 Hz to about 4 Hz, 4Hz to about 7 Hz or about 8 Hz to about 12 Hz, 18 Hz to 20 Hz, and 40Hz. The burst stimulus comprises at least two spikes, for example, eachburst stimulus can comprise about 2 to about 100 spikes, moreparticularly, about 2 to about 10 spikes. Each spike can comprise afrequency in the range of about 50 to 1000 Hz, more preferably in arange of 200 to 500 Hz. The interval between spikes (e.g., inter-spikeinterval) can be about 0.5 milliseconds to about 100 milliseconds.Preferably, the maximum inter-spike interval is 5 milliseconds. Thefrequency of the spikes within the burst does not need to be constant orregular, in fact, typically, the frequency of the spikes is random orvariable.

In further embodiments, the burst stimulus is followed by an inter-burstinterval or inter-group interval. The inter-burst interval has durationin the range of about 5 milliseconds to about 5 seconds, morepreferably, about 10 milliseconds to about 300 milliseconds. Preferably,the minimum inter-group interval is 20 milliseconds. It is envisionedthat the burst stimulus has a duration in the range of about 10milliseconds to about 5 seconds, more particular, in the range of about250 msec to 1000 msec (1-4 Hz burst firing), 145 msec to about 250 msec(4-7 Hz), 145 msec to about 80 msec (8-12 Hz) or 1 to 5 seconds inplateau potential firing. The burst stimulus and the inter-burstinterval can have a regular pattern or an irregular pattern (e.g.,random or irregular harmonics).

In certain embodiments, the neuromodulation method can be used to treatneurological disorders or diseases that result from incorrect centralnervous system control in which the disorder comprises a regularbursting rhythm. Such disorders having a regular bursting rhythminclude, but are not limited to movement disorders such as Parkinson'sDisease, epilepsy, tinnitus, central pain including phantom pain orother forms of deafferentation or central pain.

Still further, the neuromodulation method of the present invention canbe used to treat neurological disorders or diseases that result fromincorrect central nervous system control in which the disorder comprisesan irregular bursting rhythm. Such disorders can include, but are notlimited to dystonia or chorea. Still further, the neuromodulation methodof the present invention can be used to treat neurological disorders ordiseases that result from incorrect central nervous system control, andin which the methods corrects neuronal inbalances (inhibitory vsexcitatory, high frequency vs low frequency (e.g., thalamocorticaldysrhythmia), sympathetic vs parasympathetic).

The neuromodulation method of the present invention can also be used toalter a physiological and/or pathological signaling pattern. Those ofskill in the art are aware that a physiological and/or pathologicalsignaling pattern can be either regular or irregular. Thus, it isenvisioned that the stimulation method as used herein can alter suchpatterns to alleviate the neurological condition or disease.

The neuromodulation method of the present invention can be used tomodulate neuronal activity of any neuronal tissue within a patient. Incertain embodiments, a device is surgically implanted in the patientsuch that the device is in communication with a predetermined neuronaltissue site, and the device is operated to stimulate the predeterminedsite. The device can include a probe, for example, electrode assembly(e.g., electrical stimulation lead). The proximal end of the probe iscoupled to an electrical signal source, which, in turn, is operated tostimulate the predetermined treatment site.

Neuronal tissue includes any tissue associated with the peripheralnervous system or the central nervous system. Peripheral neuronal tissuecan include a nerve root, root ganglion or other nerves, for example themedian nerve, sympathetic nerve or vagal nerve, etc. Central neuronaltissue includes brain tissue, spinal tissue or brainstem tissue. Braintissue can include thalamus/sub-thalamus, basal ganglia, hippocampus,amygdala, hypothalamus, mammilary bodies, substantia nigra or cortex orwhite matter tracts afferent to or efferent from the abovementionedbrain tissue, inclusive of the corpus callosum. Spinal tissue caninclude the ascending and descending tracts of the spinal cord, morespecifically, the ascending tracts of the spinal cord that compriseintralaminar neurons or the dorsal column. The brainstem tissue caninclude the medulla oblongata, pons or mesencephalon, more particularthe posterior pons or posterior mesencephalon, Lushka's foramen, andventrolateral part of the medulla oblongata.

The foregoing has outlined rather broadly the features and technicaladvantages of the present invention in order that the detaileddescription of the invention that follows may be better understood.Additional features and advantages of the invention will be describedhereinafter which form the subject of the claims of the invention. Itshould be appreciated that the conception and specific embodimentdisclosed may be readily utilized as a basis for modifying or designingother structures for carrying out the same purposes of the presentinvention. It should also be realized that such equivalent constructionsdo not depart from the invention as set forth in the appended claims.The novel features which are believed to be characteristic of theinvention, both as to its organization and method of operation, togetherwith further objects and advantages will be better understood from thefollowing description when considered in connection with theaccompanying figures. It is to be expressly understood, however, thateach of the figures is provided for the purpose of illustration anddescription only and is not intended as a definition of the limits ofthe present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

For a more complete understanding of the present invention, reference isnow made to the following descriptions taken in conjunction with theaccompanying drawing, in which:

FIGS. 1A-1B illustrate example stimulation systems for electricallystimulating neuronal tissue.

FIGS. 2A-2I illustrate example electrical stimulation leads that may beused to electrically stimulate neuronal tissue.

FIGS. 3A-3B illustrate example neuronal firings. FIG. 3A illustrates anexample of regular neuronal firing. FIG. 3B illustrates an example of aneuronal burst firing.

FIG. 4A-4B illustrate examples of burst firing. FIG. 4A illustrate anexample of an regular burst firing pattern. FIG. 4B illustrate anexample of a irregular burst firing pattern.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

Unless defined otherwise, technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. For purposes of the presentinvention, the following terms are defined below.

As used herein, the use of the word “a” or “an” when used in conjunctionwith the term “comprising” in the claims and/or the specification maymean “one,” but it is also consistent with the meaning of “one or more,”“at least one,” and “one or more than one.” Still further, the terms“having”, “including”, “containing” and “comprising” are interchangeableand one of skill in the art is cognizant that these terms are open endedterms.

As used herein, the term “in communication” refers to the stimulationlead being adjacent, in the general vicinity, in close proximity, ordirectly next to or directly on the predetermined stimulation site.Thus, one of skill in the art understands that the lead is “incommunication” with the predetermined site if the stimulation results ina modulation of neuronal activity. The predetermined site may beselected from the group consisting of the peripheral neuronal tissue orcentral neuronal tissue. Central neuronal tissue includes, but is notlimited to brain tissue, brainstem, spinal tissue. Spinal tissueincludes, the spinal cord, or the dorsal column of the spinal cord whichmay include the spinal cord area corresponding to cervical vertebralsegments C1 to C8, thoracic vertebral segments T1 to T12, lumbarvertebral segments L1 and L2. One of ordinary skill in the art willunderstand that the spinal cord normally terminates at the second lumbarvertebrae L2. However, in certain subjects the spinal cord may terminatebefore or after the L2 vertebrae segment and that the present inventionis intended for use along the entire length of the spinal cord.

As used herein, the use of the term “dorsal column” refers to conductingpathways in the spinal cord that are located in the dorsal portion ofthe spinal cord between the posterior horns, and which comprisesafferent somatosensory neurons. The dorsal column is also known as theposterior funiculus.

As used herein, the use of the words “epidural space” or “spinalepidural space” is known to one with skill in the art, and refers to anarea in the interval between the dural sheath and the wall of the spinalcanal.

As used herein the term “modulate” refers to the ability to regulatepositively or negatively neuronal activity. Thus, the term modulate canbe used to refer to an increase, decrease, masking, altering, overridingor restoring of neuronal activity.

As used herein, the term “burst firing” or “burst mode” refers to anaction potential that is a burst of high frequency spikes (300-1000 Hz)(Beurrier et al., 1999). Burst firing acts in a non-linear fashion witha summation effect of each spike. One skilled in the art is also awarethat burst firing can also be referred to as phasic firing, rhythmicfiring (Lee 2001), pulse train firing, oscillatory firing and spiketrain firing, all of these terms used herein are interchangeable.

As used herein, the term “tonic firing” or “tonic mode” refers to anaction potential that occurs in a linear fashion.

As used herein, the term “burst” refers to a period in a spike trainthat has a much higher discharge rate than surrounding periods in thespike train (N. Urbain et al., 2002). Thus, burst can refer to aplurality of groups of spike pulses. A burst is a train of actionpotentials that, possibly, occurs during a ‘plateau’ or ‘active phase’,followed by a period of relative quiescence called the ‘silent phase’(Nunemaker, Cellscience Reviews Vol 2 No. 1, 2005). Thus, a burstcomprises spikes having an inter-spike interval in which the spikes areseparated by 0.5 milliseconds to about 100 milliseconds. Those of skillin the art realize that the inter-spike interval can be longer orshorter. Yet further, those of skill in the art also realize that thespike rate within the burst does not necessarily occur at a fixed rate;this rate can be variable.

As used herein, the term “spike” refers to an action potential. Yetfurther, a “burst spike” refers to a spike that is preceded or followedby another spike within a short time interval (Matveev, 2000), inotherwords, there is an inter-spike interval, in which this interval isgenerally about 100 ms but can be shorter or longer, for example 0.5milliseconds.

As used herein, the term “neuronal” refers to a cell which is amorphologic and functional unit of the brain, brainstem, spinal cord,and peripheral nerves.

As used herein, the term “peripheral neuronal tissue” refers to anyneuronal tissue associated with a nerve root, root ganglion, orperipheral nerve that is outside the brain and the spinal cord. Itincludes the autonomous nervous system, inclusive of (ortho-)sympatheticand parasympathetic system.

As used herein, the term “central neuronal tissue” refers to neuronaltissue associated with the brain, spinal cord or brainstem.

As used herein, the term “neurology” or “neurological” refers toconditions, disorders, and/or diseases that are associated with thenervous system. The nervous system comprises two components, the centralnervous system, which is composed of the brain and the spinal cord, andthe peripheral nervous system, which is composed of ganglia and theperipheral nerves that lie outside the brain and the spinal cord. One ofskill in the art realizes that the nervous system may be linguisticallyseparated and categorized, but functionally the system is interconnectedand interactive. Yet further, the peripheral nervous system is dividedinto the autonomic system (parasympathetic and sympathetic), the somaticsystem and the enteric system. Thus, any condition, disorder and/ordisease that effect any component or aspect of the nervous system(either central or peripheral) are referred to as a neurologicalcondition, disorder and/or disease. As used herein, the term“neurological” or “neurology” encompasses the terms “neuropsychiatric”or “neuropsychiatry” and “neuropsychological” or “neuropsychology”.Thus, a neurological disease, condition, or disorder includes, but isnot limited to tinnitus, epilepsy, depression, anxiety, Parkinson'sDisease, autonomic dysfunctions, etc.

As used herein, the term “neuropsychiatry” or “neuropsychiatric” refersto conditions, disorders and/or diseases that relate to both organic andpsychic disorders of the nervous system.

As used herein, the term “neuropsychological” or “neuropsychologic” orneuropsychology refers to conditions, disorders and/or disease thatrelate to the functioning of the brain and the cognitive processors orbehavior.

As used herein, “spinal cord,” “spinal nervous tissue associated with avertebral segment,” “nervous tissue associated with a vertebral segment”or “spinal cord associated with a vertebral segment or level” includesany spinal nervous tissue associated with a vertebral level or segment.Those of skill in the art are aware that the spinal cord and tissueassociated therewith are associated with cervical, thoracic and lumbarvertebrae. As used herein, C1 refers to cervical vertebral segment 1, C2refers to cervical vertebral segment 2, and so on. T1 refers to thoracicvertebral segment 1, T2 refers to thoracic vertebral segment 2, and soon. L1 refers to lumbar vertebral segment 1, L2 refers to lumbarvertebral segment 2, and so on, unless otherwise specifically noted. Incertain cases, spinal cord nerve roots leave the bony spine at avertebral level different from the vertebral segment with which the rootis associated. For example, the T11 nerve root leaves the spinal cordmyelum at an area located behind vertebral body T8-T9 but leaves thebony spine between T11 and T12.

As used herein, the term “stimulate” or “stimulation” refers toelectrical, chemical, magnetic, thermal and/or other such stimulationthat modulates the predetermined neuronal sites.

As used herein, the term “treating” and “treatment” refers to modulatingpredetermined neuronal sites (central neuronal tissue and/or peripheralneuronal tissue) so that the subject has an improvement in the diseaseor condition, for example, beneficial or desired clinical results. Forpurposes of this invention, beneficial or desired clinical resultsinclude, but are not limited to, alleviation of symptoms, diminishmentof extent of disease, stabilized (e.g., not worsening) state of disease,delay or slowing of disease progression, amelioration or palliation ofthe disease state, and remission (whether partial or total), whetherdetectable or undetectable. One of skill in the art realizes that atreatment may improve the disease condition, but may not be a completecure for the disease.

II. Nervous System

The nervous system comprises two general components, the central nervoussystem, which is composed of the brain and the spinal cord, and theperipheral nervous system, which is composed of ganglia or dorsal rootganglia and the peripheral nerves that lie outside the brain and thespinal cord. One of skill in the art realizes that the nervous systemmay be linguistically separated and categorized, but functionally theyare interconnected and interactive.

The central nervous system comprises the brain and spinal cord, whichtogether function as the principal integrator of sensory input and motoroutput. In general terms, the brain consists of the cerebrum (cerebralhemispheres and the diencephalons), the brainstem (midbrain, pons, andmedulla); and the cerebellum. It is well known that the cerebrumrepresents the highest center for sensory and motor and emotional andcognitive processing. In general, the frontal lobe processes motor,visual, speech, and personality modalities; the parietal lobe processessensory information; the temporal lobe, auditory and memory modalities;and the occipital lobe vision. The cerebellum, in general, coordinatessmooth motor activities and processes muscle position, while thebrainstem conveys motor and sensory information and mediates importantautonomic functions. These structures are of course integrated with thespinal cord which receives sensory input from the body and conveyssomatic and autonomic motor information to peripheral targets. Thus, oneof skill in the art realizes that the central nervous system is capableof evaluating incoming information and formulating response to changesthat threaten the homeostasis of the individual.

The peripheral nervous system is divided into the autonomic system(parasympathetic and sympathetic), the somatic system and the entericsystem. The term peripheral nerve is intended to include both motor andsensory neurons and neuronal bundles of the autonomic system, thesomatic system, and the enteric system that reside outside of the spinalcord and the brain. Peripheral nerve ganglia and nerves located outsideof the brain and spinal cord are also described by the term peripheralnerve.

A. Action Potentials and their Propagation

Information is conveyed through the nervous system via neuronal cellsalong their membranes and across synaptic junctions. Thus, the neuronalcells process information by both passive processes (e.g., electricalproperties of the membrane which enable spatial and temporal summation)and active processes (e.g., propagation of the action potential, signalamplification or attenuation, and synaptic transmission). Generation ofan action potential at the axon initial segment requires passivesummation of multiple inputs, as well as signal amplification beforemembrane depolarization reaches threshold, thus the passive and activeprocesses are interdependent.

The generation of the action potential initially depends upon theelectrical properties of the cell. It is known that cells have anelectrical voltage difference across their membranes, the membranepotential. Several types of protein pores or ion channels areresponsible for maintaining and altering the membrane potential of thecell. Voltage-gated sodium channels, which have a low threshold, areresponsible for the explosive depolarization of the membrane potentialthat forms the action potential or spike, whereas, the voltage-gatedpotassium channels are responsible for the repolarization of themembrane potential. For excitation, stimulatory input results in a netincrease in the inward flow of sodium ions compared to an outward flowof potassium ions results in a depolarizing cell membrane potentialchange. For inhibitory inputs, potassium and chloride ion channels areopened which drives the membrane potential away from threshold(hyperpolarization). As one of skill in the art realizes neurons receivemultiple excitatory and inhibitory inputs, thus summation of theseinputs occurs, for example temporal and spatial summation. Temporalsummation occurs when a series of subthreshold impulses in oneexcitatory fiber produces an action potential in postsynaptic cell.Spatial summation occurs when subthreshold impulses from two or moredifferent fibers trigger an action potential.

Once the initial action potential is generated, the information isconveyed via axonal conduction or synaptic transmission (e.g., chemicalor electrical). Electrical synapses are found not only in the brain, butin heart and smooth muscle and epithelial liver cells. However, in thebrain, electrical synapses (also known as gap junctions) are less commonthan chemical synapses, and are characterized by rapid speed oftransmission and do not readily allow inhibitory actions or long-lastingchanges in effectiveness. Gap junctions allow the passage of not onlyions, but other small molecules. In humans, astrocytes contain gapjunctions to mediate potassium buffering, and they are also present inthe retina, inferior olive, vestibular nuclei, nucleus of the trigeminalnerve, and the reticular nucleus of the thalamus.

Chemical synapses, on the contrary, do mediate either excitatory orinhibitory actions, and are generally considered more flexible. Anotherdifference between chemical and electrical transmission is thatelectrical can be bidirectional since the ion channels connect thecytoplasm of the pre and postsynaptic cells, whereas chemicaltransmission is typically unidirectional since there is no continuitybetween the cells. Chemical synapses comprise a presynaptic element thatcontain vesicles comprising neurotransmitters and a postsynaptic elementwhich contains receptors for the neurotransmitters. Transmitter releaseis initiated when the nerve terminal is depolarized by an actionpotential resulting in a rapid influx of calcium ions into the nerveterminal. This rapid influx of calcium ions cause fusion of the vesiclesto the presynaptic membrane and ultimately release of theneurotransmitters which then bind to their receptor located on thepostsynaptic membrane.

The ability of the neuronal cell to fire or produce action potentialsmay vary depending upon its biophysical properties (e.g., types of ionicchannels, etc.) and/or its position in the circuit or nervous system.Thus, cells can respond to an input (stimulatory or inhibitory) with adecelerating train of action potentials, an accelerating train of actionpotentials or a constant firing frequency. For example, an increase infiring of a neuronal cell may be a result from increased amounts ofcalcium ions or a function of residual increase in calcium ions leftover from the first stimulation (also known as facilitation) in thepresynaptic element which results in increase release ofneurotransmitter. Thus, a second stimulation can occur withinmilliseconds of the first. Conversely, a second stimulation may resultin inhibition and not facilitation of the response if an inhibitoryinterneuron is activated which feedback to the first neuronal cell toinhibit firing.

B. Firing Modes

Different firing modes or frequencies occur in the brain and/or otherneuronal tissue, for example tonic firing and burst firing (irregular orregular burst firing), as shown in FIGS. 3 and 4. The thalamus utilizesboth types of firing modes. The two thalami (bilateral pairedstructures) are the gateways to the cerebral cortex and, thus, toconsciousness. The thalamic nuclei specialize in several differentsignaling functions: transmitting signals from sensory input to thecortex; transmitting signals from cortical motor centers to effectors;transmitting control signals that select which input and output will bepermitted to pass to and from the cortex and how the signals will besequenced (thalamic reticular nuclei (TRN)); and modulating (controllingintensity) and synchronizing (grouping) the signals (Intralaminar Nuclei(ILN)).

All thalamic relay neurons pass through the TRN, which opens and closestheir “gates” going to the cortex, (McAlonan and Brown, 2002). One modethat TRN neurons use to transmit these relays is burst firing mode. Thismode is useful for activating a small population of neurons in thecortex for a short period. In contrast, the continuous (tonic) firingmode permits a thalamic neuron to transmit a steady stream of signals tothe cortex. The tonic firing pattern triggers looping activation in thecortical circuits that receive the signals. Evoking looping, or“recurrent” activation in the cortex requires a steady neural input.

The ILN are a tiny cluster of cells in the central body of the thalamus,hidden inside of the “laminae,” the white layers that separate thebigger nuclei of the thalamus. In contrast to the bigger relay nuclei,most of the ILN send signals that change the activity of the corticalreceiving area (Sherman and Guillery, 2002). For example, an ILN mightreceive signals from one cortical area and send them on to several othercortical areas to increase excitation in the receiving areas (acortico-thalamocortical pattern, C-T-C).

Tonic or burst firing mode may be related to the molecules which areassociated with the neurons. Such molecules include either parvalbumin(an egg-derived protein also a calcium-binding protein) or calbindin (acalcium-binding protein). Tonic firing is found especially in cells thatcontain parvalbumin. It behaves in a linear fashion, for example, theauditory thalamus (MGBV) fires at a specific frequency and the auditorycortex will follow at the same pace with a minor phase difference(Miller et al., 2001) of 2 ms. Tonic firing, however, can be overruledby burst firing (Lisman 1997; Sherman 2001; Swadlow and Gusev 2001).

Burst firing is typically found in calbindin positive cells (Kawaguchiand Kubota 1993; Hu et al., 1994; Hu 1995; He and Hu 2002). Thus, burstmode firing may utilize a calbindin system to generate the burst.Generally, burst firing is accomplished through the activation of eithera subthreshold membrane conductance that initiates action potentials ora suprathreshold membrane conductance that once activated evokes two ormore action potentials. Sodium (Na⁺) and calcium (Ca²⁺) activatedconductances have all been implicated in burst generation. Hippocampal(Wong and Stewart, 1992; Traub et al., 1994) and layer V neocortical(Schwindt and Crill, 1999) pyramidal cells may initiate somatic Na⁺action potentials from a slow Ca²⁺ potential generated within thedendrites. Alternatively, bursts in subicular (Mattia et al., 1997) andsensorimotor cortical neurons (Franceschetti et al., 1995; Guatteo etal., 1996) may be generated through a voltage-dependent Na⁺ conductance,independent of Ca²⁺ (Brumberg, 2000).

Burst firing acts in a non-linear fashion (Lisman 1997; Sherman 2001;Swadlow and Gusev 2001) with a summation effect of each spike, thus morereadily activating a target cell (Lisman 1997) than tonic firing. Burstfiring has been described in drowsiness, slow wave sleep, and anesthesia(Steriade et al., 1989; McCormick and Feeser 1990), as well as epilepsy(Futatsugi and Riviello 1998; Huguenard 1999) in the thalamus, and itfunctionally shuts off external auditory sensory stimuli to gain accessto the cortex (Edeline et al., 2000; Massaux and Edeline 2003; Massauxet al. 2004), though not completely (Edeline et al., 2000). Neuralnetwork modeling has further demonstrated that bursts are generated bypositive feedback through excitatory connections (Tabak and Latham2003). In networks of two populations, one excitatory and oneinhibitory, decreasing the inhibitory feedback can cause the network toswitch from a tonically active, asynchronous state to the synchronizedbursting state (van Vreeswijk and Hansel 2001).

The generation of repetitive burst discharges in neurons is correlatedwith the generation of gamma frequency (30-70 Hz) oscillations in thelocal field potential (Gray and Singer, 1989). It is believed thatconscious perception depends on gamma band frequency activity (Gray andSinger, 1989; Joliot, 1994; Steriade, 2000).

Increasing depolarization to hyperpolarization induces a prolongedrefractory period of tonic firing resulting in single spike bursts(Ramcharan, Cox et al., 2000) (in the visual system), furtherdepolarization results in progressively more spikes per burst(Ramcharan, Cox et al., 2000). Further depolarization will silence thecell (Beurrier, Congar et al. 1999).

The transient membrane hyperpolarization leads to activation of voltagedependent T type calcium channels generating low threshold calciumspikes. Riding on top of the low thresholds calcium spikes are bursts ofsodium spikes mediated by fast voltage-gated sodium channels (Steriadeand Llinas 1988). Calcium entry during the burst leads to calciumactivated potassium channels then in combination with voltage gatedpotassium channels the membrane is repolarized (McCormick and Feeser1990). The low threshold calcium spikes act as a pacemaker (Perez-Reyes2003).

It is hypothesized according to the present invention that burststimulation may be used by neuronal tissue to process information in amanner that is similar to amplitude modulation. Specifically, thespacing between individual bursts in a burst stimulus may be used tosignal information to various regions in the brain. That is, the spacingbetween the bursts can vary (hence are “amplitude modulated”) to conveyinformation. The signaled information can be related to relevanceinformation. The signaled information could also be related to signalingthe beginning and ending of certain packets of information. By providingelectrical burst stimulation from an implantable pulse generator, it ispossible that the stimulated brain tissue will change its processing ofother stimulus information. For example, by appropriately selecting aninterburst interval, auditory information that would otherwise beproblematic to a patient could become ignored by a respective segment ofthe brain due to a lack of “relevance” and/or a lack of synchronizationwith the arrival of the burst stimulus.

III. Electrical Stimulation Devices

FIGS. 1A-1B illustrate example neurological stimulation systems 10 forelectrically stimulating a predetermined site area to treat one or moreneurological disorders or conditions. In general terms, stimulationsystem 10 includes an implantable pulse generating source or electricalstimulation source 12 and one or more implantable electrodes orelectrical stimulation leads 14 for applying electrical stimulationpulses to the a predetermined site. In operation, both of these primarycomponents are implanted in the person's body, as discussed below. Incertain embodiments, stimulation source 12 is coupled directly to aconnecting portion 16 of stimulation lead 14. In certain otherembodiments, stimulation source 12 is incorporated into the stimulationlead 14 and stimulation source 12 instead is embedded within stimulationlead 14. For example, such a stimulation system 10 may be a Bion®stimulation system manufactured by Advanced Bionics Corporation. Whetherstimulation source 12 is coupled directly to or embedded within thestimulation lead 14, stimulation source 12 controls the stimulationpulses transmitted to one or more stimulation electrodes 18 located on astimulating portion 20 of stimulation lead 14, positioned incommunication with a predetermined site, according to suitablestimulation parameters (e.g., duration, amplitude or intensity,frequency, pulse width, etc.).

As contemplated in the present invention, a predetermined site caninclude either peripheral neuronal tissue and/or central neuronaltissue. Neuronal tissue includes any tissue associated with theperipheral nervous system or the central nervous system. Peripheralneuronal tissue can include a nerve root or root ganglion or anyneuronal tissue that lies outside the brain, brainstem or spinal cord.Peripheral nerves can include, but are not limited to olfactory nerve,optic, nerve, oculomotor nerve, trochlear nerve, trigeminal nerve,abducens nerve, facial nerve, vestibulocochlear (auditory) nerve,glossopharyngeal nerve, vagal nerve, accessory nerve, hypoglossal nerve,suboccipital nerve, the greater occipital nerve, the lesser occipitalnerve, the greater auricular nerve, the lesser auricular nerve, thephrenic nerve, brachial plexus, radial axillary nerves, musculocutaneousnerves, radial nerves, ulnar nerves, median nerves, intercostal nerves,lumbosacral plexus, sciatic nerves, common peroneal nerve, tibialnerves, sural nerves, femoral nerves, gluteal nerves, thoracic spinalnerves, obturator nerves, digital nerves, pudendal nerves, plantarnerves, saphenous nerves, ilioinguinal nerves, gentofemoral nerves, andiliohypogastric nerves.

Central neuronal tissue includes brain tissue, spinal tissue orbrainstem tissue. Brain tissue can include thalamus/sub-thalamus, basalganglia, hippocampus, amygdala, hypothalamus, mammilary bodies,substantia nigra or cortex or white matter tracts afferent to orefferent from the abovementioned brain tissue, inclusive of the corpuscallosum. Spinal tissue can include the ascending and descending tractsof the spinal cord, more specifically, the ascending tracts of thatcomprise intralaminar neurons or the dorsal column. The brainstem tissuecan include the medulla oblongata, pons or mesencephalon, moreparticular the posterior pons or posterior mesencephalon, Lushka'sforamen, and ventrolateral part of the medulla oblongata.

A doctor, the patient, or another user of stimulation source 12 maydirectly or indirectly input stimulation parameters to specify or modifythe nature of the stimulation provided.

In one embodiment, as shown in FIG. 1A, stimulation source 12 includesan implantable pulse generator (IPG). One of skill in the art is awarethat any commercially available implantable pulse generator can be usedin the present invention, as well as a modified version of anycommercially available pulse generator. Thus, one of skill in the artwould be able to modify an IPG to achieve the desired results. Anexemplary IPG is one that is manufactured by Advanced NeuromodulationSystems, Inc., such as the Genesis□ System, part numbers 3604, 3608,3609, and 3644. Another example of an IPG is shown in FIG. 1B, whichshows stimulation source 12 including an implantable wireless receiver.An example of a wireless receiver may be one manufactured by AdvancedNeuromodulation Systems, Inc., such as the Renew□ System, part numbers3408 and 3416. In another embodiment, the IPG can be optimized for highfrequency operation as described in U.S. Provisional Application Ser.No. 60/685,036, filed May 26, 2005, entitled “SYSTEMS AND METHODS FORUSE IN PULSE GENERATION,” which is incorporated herein by reference. Thewireless receiver is capable of receiving wireless signals from awireless transmitter 22 located external to the person's body. Thewireless signals are represented in FIG. 1B by wireless link symbol 24.A doctor, the patient, or another user of stimulation source 12 may usea controller 26 located external to the person's body to provide controlsignals for operation of stimulation source 12. Controller 26 providesthe control signals to wireless transmitter 22, wireless transmitter 22transmits the control signals and power to the wireless receiver ofstimulation source 12, and stimulation source 12 uses the controlsignals to vary the signal parameters of electrical signals transmittedthrough electrical stimulation lead 14 to the stimulation site. Thus,the external controller 26 can be for example, a handheld programmer, toprovide a means for programming the IPG. An example wireless transmitter122 may be one manufactured by Advanced Neuromodulation Systems, Inc.,such as the Renew□ System, part numbers 3508 and 3516.

Conventional neuromodulation devices can be modified to apply burststimulation to nerve tissue of a patient by modifying the softwareinstructions stored in the devices. Specifically, conventionalneuromodulation devices typically include a microprocessor and a pulsegeneration module. The pulse generation module generates the electricalpulses according to a defined pulse width and pulse amplitude andapplies the electrical pulses to defined electrodes. The microprocessorcontrols the operations of the pulse generation module according tosoftware instructions stored in the device.

These conventional neuromodulation devices can be adapted by programmingthe microprocessor to deliver a number of spikes (relatively short pulsewidth pulses) that are separated by an appropriate interspike interval.Thereafter, the programming of the microprocessor causes the pulsegeneration module to cease pulse generation operations for an interburstinterval. The programming of the microprocessor also causes a repetitionof the spike generation and cessation of operations for a predeterminednumber of times. After the predetermined number of repetitions have beencompleted, the microprocessor can cause burst stimulation to cease foran amount of time (and resume thereafter). Also, in some embodiments,the microprocessor could be programmed to cause the pulse generationmodule to deliver a hyperpolarizing pulse before the first spike of eachgroup of multiple spikes.

The microprocessor can be programmed to allow the variouscharacteristics of the burst stimulus to be set by a physician to allowthe burst stimulus to be optimized for a particular pathology of apatient. For example, the spike amplitude, the interspike interval, theinterburst interval, the number of bursts to be repeated in succession,the amplitude of the hyperpolarizing pulse, and other suchcharacteristics could be controlled using respective parameters accessedby the microprocessor during burst stimulus operations. These parameterscould be set to desired values by an external programming device viawireless communication with the implantable neuromodulation device.

In another embodiment, a neuromodulation device can be implemented toapply burst stimulation using a digital signal processor and one orseveral digital-to-analog converters. The burst stimulus waveform couldbe defined in memory and applied to the digital-to-analog converter(s)for application through electrodes of the medical lead. The digitalsignal processor could scale the various portions of the waveform inamplitude and within the time domain (e.g., for the various intervals)according to the various burst parameters.

FIGS. 2A-2I illustrate example stimulation leads 14 that may be used forelectrically stimulating the predetermined site to treat one or moreneurological disorders or conditions. As described above, each of theone or more stimulation leads 14 incorporated in stimulation system 10includes one or more stimulation electrodes 18 adapted to be positionedin communication with the predetermined site and used to deliver to thestimulation pulses received from stimulation source 12. A percutaneousstimulation lead 14, such as example stimulation leads 14 a-d, includesone or more circumferential electrodes 18 spaced apart from one anotheralong the length of stimulating portion 20 of stimulation lead 14.Circumferential electrodes 18 emit electrical stimulation energygenerally radially (e.g., generally perpendicular to the axis ofstimulation lead 14) in all directions. A laminotomy, paddle, orsurgical stimulation lead 14, such as example stimulation leads 14 e-i,includes one or more directional stimulation electrodes 18 spaced apartfrom one another along one surface of stimulation lead 14. Directionalstimulation electrodes 18 emit electrical stimulation energy in adirection generally perpendicular to the surface of stimulation lead 14on which they are located. Although various types of stimulation leads14 are shown as examples, the present invention contemplates stimulationsystem 10 including any suitable type of stimulation lead 14 in anysuitable number. In addition, stimulation leads 14 may be used alone orin combination. For example, medial or unilateral stimulation of thepredetermined site may be accomplished using a single electricalstimulation lead 14 implanted in communication with the predeterminedsite in one side of the head, while bilateral electrical stimulation ofthe predetermined site may be accomplished using two stimulation leads14 implanted in communication with the predetermined site in oppositesides of the head.

In one embodiment, the stimulation source is transcutaneously incommunication with the electrical stimulation lead. In “transcutaneous”electrical nerve stimulation (TENS), the stimulation source is externalto the patient's body, and may be worn in an appropriate fanny pack orbelt, and the electrical stimulation lead is in communication with thestimulation source, either remotely or directly. In another embodiment,the stimulation is percutaneous. In “percutaneous” electrical nervestimulation (PENS), needles are inserted to an appropriate depth aroundor immediately adjacent to a predetermined stimulation site, and thenstimulated.

In addition to electrical stimulation, other forms of stimulation can beused, for example magnetic. Magnetic stimulation can be provided byinternally implanted probes or by externally applied directed magneticfields, for example, U.S. Pat. Nos. 6,592,509; 6,132,361; 5,752,911; and6,425,852, each of which is incorporated herein in its entirety. Quickpulses of magnetic stimulation can be applied externally ortranscranially, for example repetitive transcranially magneticstimulation (rTMS).

Whether using percutaneous leads, laminotomy leads, or some combinationof both, the leads are coupled to one or more conventionalneurostimulation devices, or signal generators. The devices can betotally implanted systems and/or radio frequency (RF) systems. Anexample of an RF system is a MNT/MNR-916CC system manufactured byAdvanced Neuromodulation Systems, Inc.

The preferred neurostimulation devices should allow each electrode ofeach lead to be defined as a positive, a negative, or a neutralpolarity. For each electrode combination (e.g., the defined polarity ofat least two electrodes having at least one cathode and at least oneanode), an electrical signal can have at least a definable amplitude(e.g., voltage), pulse width, and frequency, where these variables maybe independently adjusted to finely select the sensory transmittingnerve tissue required to inhibit transmission of neuronal signals.Generally, amplitudes, pulse widths, and frequencies are determinable bythe capabilities of the neurostimulation systems, which are known bythose of skill in the art. Voltages that may be used can include, forexample about 0.5 to about 10 volts, more preferably about 1 to about 10volts.

In the present invention, the stimulation parameter of signalfrequencies are varied to achieve a burst type rhythm, or burst modestimulation, as shown in FIG. 3B. Generally, the burst stimulusfrequency may be in the range of about 1 Hz to about 100 Hz, moreparticular, in the range of about 1 Hz to about 12 Hz, and moreparticularly, in the range of about 1 Hz to about 4 Hz, 4 Hz to about 7Hz or about 8 Hz to about 12 Hz for each burst. One skilled in the artwill further realize that each burst stimulus comprises at least twospikes, for example, each burst stimulus can comprise about 2 to about100 spikes, more particularly, about 2 to about 10 spikes. Each spikecan comprise a frequency in the range of about 50 Hz to about 1000 Hz,more particularly, in the range of about 200 Hz to about 500 Hz. One ofskill in the art is aware that the frequency for each spike within aburst can be variable, thus it is not necessary for each spike tocontain similar frequencies, e.g., the frequencies can vary in eachspike. The inter-spike interval can be also vary, for example, theinter-spike interval, can be about 0.5 milliseconds to about 100milliseconds or any range therebetween.

The burst stimulus can be followed by an inter-burst interval, as shownin FIGS. 4A-4B. The inter-burst interval has duration in the range ofabout 5 milliseconds to about 5 seconds, more preferably, 10milliseconds to about 300 milliseconds. It is envisioned that the burststimulus has a duration in the range of about 10 milliseconds to about 5seconds, more particular, in the range of about 250 msec to 1000 msec(1-4 Hz burst firing), 145 msec to about 250 msec (4-7 Hz), 145 msec toabout 80 msec (8-12 Hz) or 1 to 5 seconds in plateau potential firing.The burst stimulus and the inter-burst interval can have a regularpattern or an irregular pattern (e.g., random or irregular harmonics),as shown in FIGS. 4A-4B. More specifically, the burst stimulus can havea physiological pattern or a pathological pattern.

It is envisaged that the patient will require intermittent assessmentwith regard to patterns of stimulation. Different electrodes on the leadcan be selected by suitable computer programming, such as that describedin U.S. Pat. No. 5,938,690, which is incorporated by reference here infull. Utilizing such a program allows an optimal stimulation pattern tobe obtained at minimal voltages. This ensures a longer battery life forthe implanted systems.

IV. Implantation of Electrical Devices

The stimulation system 10, described above, can be implanted into aperson's body with stimulation lead 14 located in communication with apredetermined site. It is envisioned that the predetermined site can bea central or peripheral neuronal tissue.

A. Deep Brain Stimulation

In certain embodiments, for example, patients who are to have anelectrical stimulation lead or electrode implanted into the brain,generally, first have a stereotactic head frame, such as the Leksell,CRW, or Compass, mounted to the patient's skull by fixed screws.However, frameless techniques may also be used. Subsequent to themounting of the frame, the patient typically undergoes a series ofmagnetic resonance imaging sessions, during which a series of twodimensional slice images of the patient's brain are built up into aquasi-three dimensional map in virtual space. This map is thencorrelated to the three dimensional stereotactic frame of reference inthe real surgical field. In order to align these two coordinate frames,both the instruments and the patient must be situated in correspondenceto the virtual map. The current way to do this is to rigidly mount thehead frame to the surgical table. Subsequently, a series of referencepoints are established to relative aspects of the frame and patient'sskull, so that either a person or a computer software system can adjustand calculate the correlation between the real world of the patient'shead and the virtual space model of the patient MRI scans. The surgeonis able to target any region within the stereotactic space of the brainwith precision (e.g., within 1 mm). Initial anatomical targetlocalization is achieved either directly using the MRI images orfunctional imaging (PET or SPECTscan, fMRI, MSI), or indirectly usinginteractive anatomical atlas programs that map the atlas image onto thestereotactic image of the brain. As is described in greater detailelsewhere in this application, the anatomical targets or predeterminedsite may be stimulated directly or affected through stimulation inanother region of the brain.

In preferred embodiments, the predetermined site or implant sitesinclude, but are not limited to thalamus/sub-thalamus, basal ganglia,hippocampus, amygdala, hypothalamus, mammilary bodies, substantia nigraor cortex or white matter tracts afferent to or efferent from theabovementioned brain tissue, inclusive of the corpus callosum. Stillfurther, the predetermined site may comprise the auditory cortex and/orsomatosensory cortex in which the stimulation devices is implantedcortically.

Based upon the coordinates, the electrical stimulation lead 14 can bepositioned in the brain. Typically, an insertion cannula for electricalstimulation lead 14 is inserted through the burr hole into the brain,but a cannula is not required. For example, a hollow needle may providethe cannula. The cannula and electrical stimulation lead 14 may beinserted together or lead 14 may be inserted through the cannula afterthe cannula has been inserted.

Once electrical stimulation lead 14 has been positioned in the brain,lead 14 is uncoupled from any stereotactic equipment present, and thecannula and stereotactic equipment are removed. Where stereotacticequipment is used, the cannula may be removed before, during, or afterremoval of the stereotactic equipment. Connecting portion 16 ofelectrical stimulation lead 14 is laid substantially flat along theskull. Where appropriate, any burr hole cover seated in the burr holemay be used to secure electrical stimulation lead 14 in position andpossibly to help prevent leakage from the burr hole and entry ofcontaminants into the burr hole. Example burr hole covers that may beappropriate in certain embodiments are illustrated and described inco-pending U.S. application Ser. Nos. 11/010,108 and 11/010,136, bothfiled Dec. 10, 2004 and entitled “Electrical Stimulation System andAssociated Apparatus for Securing an Electrical Stimulation Lead inPosition in a Person's Brain”, both of which are incorporated herein intheir entirety.

Once electrical stimulation lead 14 has been inserted and secured,connecting portion 16 of lead 14 extends from the lead insertion site tothe implant site at which stimulation source 12 is implanted. Theimplant site is typically a subcutaneous pocket formed to receive andhouse stimulation source 12. The implant site is usually positioned adistance away from the insertion site, such as near the chest, below theclavicle or alternatively near the buttocks or another place in thetorso area. Once all appropriate components of stimulation system 10 areimplanted, these components may be subject to mechanical forces andmovement in response to movement of the person's body. A doctor, thepatient, or another user of stimulation source 12 may directly orindirectly input signal parameters for controlling the nature of theelectrical stimulation provided.

Although example steps are illustrated and described, the presentinvention contemplates two or more steps taking place substantiallysimultaneously or in a different order. In addition, the presentinvention contemplates using methods with additional steps, fewer steps,or different steps, so long as the steps remain appropriate forimplanting an example stimulation system 10 into a person for electricalstimulation of the person's brain.

B. Spinal and Peripheral Neuronal Tissue

Electrical energy can be delivered through electrodes positionedexternal to the dura layer surrounding the spinal cord. Stimulation onthe surface of the cord (subdurally) is also contemplated, for example,stimulation may be applied to the dorsal columns as well as to thedorsal root entry zone or the dorsal root ganglia and/or nerve root. Anyarea of the spinal cord may be stimulated in the present invention forexample the any neuronal tissue associated with any of the cervicalvertebral segments (C1, C2, C3, C4, C5, C6, C7 and C8) and/or any tissueassociated with any of the thoracic vertebral segments (T1, T2, T3, T4,T5, T6, T7, T8, T9, T10, T11, 12) and/or any tissue associated with anyof the lumbar vertebral segments (L1, L2, L3, L4. L5, L6) and/or anytissue associated with the sacral vertebral segments (S1, S2, S3, S4,S5). Peripheral nerves can include, but are not limited to olfactorynerve, optic, nerve, oculomotor nerve, trochlear nerve, trigeminalnerve, abducens nerve, facial nerve, vestibulocochlear (auditory) nerve,glossopharyngeal nerve, vagal nerve, accessory nerve, hypoglossal nerve,suboccipital nerve, the greater occipital nerve, the lesser occipitalnerve, the greater auricular nerve, the lesser auricular nerve, thephrenic nerve, brachial plexus, radial axillary nerves, musculocutaneousnerves, radial nerves, ulnar nerves, median nerves, intercostal nerves,lumbosacral plexus, sciatic nerves, common peroneal nerve, tibialnerves, sural nerves, femoral nerves, gluteal nerves, thoracic spinalnerves, obturator nerves, digital nerves, pudendal nerves, plantarnerves, saphenous nerves, ilioinguinal nerves, gentofemoral nerves, andiliohypogastric nerves. In addition peripheral nerves also includes thenerves of the autonomic nervous system, including both sympathetic andparasympathetic system

Stimulation electrodes 18 may be positioned in various body tissues andin contact with various tissue layers; for example, subdural,subarachnoid, epidural, cutaneous, transcutaneous and subcutaneousimplantation is employed in some embodiments. The electrodes are carriedby two primary vehicles: a percutaneous leads and a laminotomy lead.

In certain embodiments, one or more stimulation electrodes 18 arepositioned in communication with a peripheral nerve. Stimulationelectrodes 18 are commonly positioned in communication with theperipheral nerve by electrodes applied cutaneously to the dermatome areaof a peripheral nerve. Stimulation electrodes 18 can be positionedsubcutaneously in communication with the peripheral nerve or on thenerve root ganglion.

For spinal cord stimulation, percutaneous leads commonly have two ormore, equally-spaced electrodes, which are placed above the dura layerthrough the use of a Touhy-like needle. For insertion, the Touhy-likeneedle is passed through the skin, between desired vertebrae, to openabove the dura layer. For unilateral stimulation, percutaneous leads arepositioned on a side of a spinal column corresponding to the “afflicted”side of the body, as discussed above, and for bilateral stimulation, asingle percutaneous lead is positioned along the patient midline (or twoor more leads are positioned on each side of the midline).

An example of an eight-electrode percutaneous lead is an OCTRODE® leadmanufactured by Advanced Neuromodulation Systems, Inc. A stimulationsystem such as is described in U.S. Pat. No. 6,748,276 is alsocontemplated.

Laminotomy leads have a paddle configuration and typically possess aplurality of electrodes (for example, two, four, eight, or sixteen)arranged in one or more columns. An example of a sixteen-electrodelaminotomy lead is shown in FIG. 2.

Implanted laminotomy leads are commonly transversely centered over thephysiological midline of a patient. In such position, multiple columnsof electrodes are well suited to address both unilateral and bilateralstimulation requirements, where electrical energy may be administeredusing either column independently (on either side of the midline) oradministered using both columns to create an electric field whichtraverses the midline. A multi-column laminotomy lead enables reliablepositioning of a plurality of electrodes, and in particular, a pluralityof electrode columns that do not readily deviate from an initialimplantation position.

Laminotomy leads require a surgical procedure for implantation. Thesurgical procedure, or partial laminectomy, requires the resection andremoval of certain vertebral tissue to allow both access to the dura andproper positioning of a laminotomy lead. The laminotomy lead offers amore stable platform, which is further capable of being sutured inplace, that tends to migrate less in the operating environment of thehuman body. Unlike the needle-delivered percutaneous leads, laminotomyleads have a paddle configuration. The paddle typically possess aplurality of electrodes (for example, two, four, eight, or sixteen)arranged in some pattern, for example, columns. An example of aneight-electrode, two column laminotomy lead is a LAMITRODE® 44 leadmanufactured by Advanced Neuromodulation Systems, Inc.

In the context of conventional spinal cord stimulation, the surgicalprocedure, or partial laminectomy, requires the resection and removal ofcertain vertebral tissue to allow both access to the dura and properpositioning of a laminotomy lead. Depending on the position ofinsertion, however, access to the dura may only require a partialremoval of the ligamentum flavum at the insertion site.

If necessary, stimulation source 12 may be coupled directly toconnecting portion 16 of stimulation lead 14. Alternatively, asdescribed above and if necessary, stimulation source 12 may not becoupled directly to stimulation lead 14 and may instead be coupled tostimulation lead 14 via an appropriate wireless link. Of course, asthose skilled in the art know, an embedded stimulation system will notneed to be so coupled.

C. Brainstem Stimulation

The stimulation system 10, described above, can be implanted into aperson's body with stimulation lead 14 located in communication with apredetermined brainstem tissue and/or area. Such systems that can beused are described in WO2004062470, which is incorporated herein byreference in its entirety.

The predetermined brainstem tissue can be selected from medullaoblongata, pons or mesencephalon, more particular the posterior pons orposterior mesencephalon, Lushka's foramen, and ventrolateral part of themedulla oblongata.

Implantation of a stimulation lead 14 in communication with thepredetermined brainstem area can be accomplished via a variety ofsurgical techniques that are well known to those of skill in the art.For example, an electrical stimulation lead can be implanted on, in, ornear the brainstem by accessing the brain tissue through a percutaneousroute, an open craniotomy, or a burr hole. Where a burr hole is themeans of accessing the brainstem, for example, stereotactic equipmentsuitable to aid in placement of an electrical stimulation lead 14 on,in, or near the brainstem may be positioned around the head. Anotheralternative technique can include, a modified midline or retrosigmoidposterior fossa technique.

In certain embodiments, electrical stimulation lead 14 is located atleast partially within or below the aura mater adjacent the brainstem.Alternatively, a stimulation lead 14 can be placed in communication withthe predetermined brainstem area by threading the stimulation lead upthe spinal cord column, as described above, which is incorporatedherein.

As described above, each of the one or more leads 14 incorporated instimulation system 10 includes one or more electrodes 18 adapted to bepositioned near the target brain tissue and used to deliver electricalstimulation energy to the target brain tissue in response to electricalsignals received from stimulation source 12. A percutaneous lead 14 mayinclude one or more circumferential electrodes 18 spaced apart from oneanother along the length of lead 14. Circumferential electrodes 18 emitelectrical stimulation energy generally radially in all directions andmay be inserted percutaneously or through a needle. The electrodes 18 ofa percutaneous lead 14 may be arranged in configurations other thancircumferentially, for example as in a “coated” lead 14. A laminotomy orpaddle style lead 14, such as example leads 14 e-i, includes one or moredirectional electrodes 18 spaced apart from one another along onesurface of lead 14. Directional electrodes 18 emit electricalstimulation energy in a direction generally perpendicular to the surfaceof lead 14 on which they are located. Although various types of leads 14are shown as examples, the present invention contemplates stimulationsystem 10 including any suitable type of lead 14 in any suitable number,including three-dimensional leads and matrix leads as described below.In addition, the leads may be used alone or in combination.

Yet further, a stimulation lead 14 can be implanted in communicationwith the predetermined brainstem area by a using stereotactic proceduressimilar to those described above, which are incorporated herein, forimplantation via the cerebrum.

Still further, a predetermined brainstem area can be indirectlystimulated by implanting a stimulation lead 14 in communication with acranial nerve (e.g., olfactory nerve, optic, nerve, oculomoter nerve,trochlear nerve, trigeminal nerve, abducent nerve, facial nerve,vestibulocochlear nerve, glossopharyngeal nerve, vagal nerve, accessorynerve, and the hypoglossal nerve) as well as high cervical nerves(cervical nerves have anastomoses with lower cranial nerves) such thatstimulation of a cranial nerve indirectly stimulates the predeterminedbrainstem tissue. Such techniques are further described in U.S. Pat.Nos. 6,721,603; 6,622,047; and 5,335,657, and U.S. ProvisionalApplication 60/591,195 entitled “Stimulation System and Method forTreating a Neurological Disorder” each of which are incorporated hereinby reference.

Although example steps are illustrated and described, the presentinvention contemplates two or more steps taking place substantiallysimultaneously or in a different order. In addition, the presentinvention contemplates using methods with additional steps, fewer steps,or different steps, so long as the steps remain appropriate forimplanting stimulation system 10 into a person for electricalstimulation of the predetermined site.

V. Infusion Pumps

In further embodiments, it may be desirable to use a drug deliverysystem independently or in combination with electrical stimulation toresult in the stimulation parameters of the present invention. Drugdelivery may be used independent of or in combination with alead/electrode to provide electrical stimulation and chemicalstimulation. When used, the drug delivery catheter is implanted suchthat the proximal end of the catheter is coupled to a pump and adischarge portion for infusing a dosage of a pharmaceutical or drug.Implantation of the catheter can be achieved by combining data from anumber of sources including CT, MRI or conventional and/or magneticresonance angiography into the stereotactic targeting model. Thus,implantation of the catheter can be achieved using similar techniques asdiscussed above for implantation of electrical leads, which isincorporated herein. The distal portion of the catheter can havemultiple orifices to maximize delivery of the pharmaceutical whileminimizing mechanical occlusion. The proximal portion of the cathetercan be connected directly to a pump or via a metal, plastic, or otherhollow connector, to an extending catheter.

Any type of infusion pump can be used in the present invention. Forexample, “active pumping” devices or so-called peristaltic pumps aredescribed in U.S. Pat. Nos. 4,692,147, 5,840,069, and 6,036,459, whichare incorporated herein by reference in their entirety. Peristalticpumps are used to provide a metered amount of a drug in response to anelectronic pulse generated by control circuitry associated within thedevice. An example of a commercially available peristaltic pump isSynchroMed® implantable pump from Medtronic, Inc., Minneapolis, Minn.

Other pumps that may be used in the present invention includeaccumulator-type pumps, for example certain external infusion pumps fromMinimed, Inc., Northridge, Calif. and Infusaid® implantable pump fromStrato/Infusaid, Inc., Norwood, Mass. Passive pumping mechanisms can beused to release an agent in a constant flow or intermittently or in abolus release. Passive type pumps include, for example, but are notlimited to gas-driven pumps described in U.S. Pat. Nos. 3,731,681 and3,951,147; and drive-spring diaphragm pumps described in U.S. Pat. Nos.4,772,263, 6,666,845, 6,620,151 all of which are incorporated byreference in their entirety. Pumps of this type are commerciallyavailable, for example, Model 3000® from Arrow International, Reading,Pa. and IsoMed® from Medtronic, Inc., Minneapolis, Minn.; AccuRx® pumpfrom Advanced Neuromodulation Systems, Inc., Plano, Tex.

In certain embodiments, the catheter can be in the form of a leadcatheter combination, similar to the ones described in U.S. Pat. No.6,176,242 and U.S. Pat. No. 5,423,877, which are incorporated herein byreference in their entirety.

Still further, the present invention can comprise a chemical stimulationsystem that comprises a system to control release of neurotransmitters(e.g., glutamate, acetylcholine, norepinephrine, epinephrine), chemicals(e.g., zinc, magnesium, lithium) and/or pharmaceuticals that are knownto alter the activity of neuronal tissue. For example, infusionformulation delivery system can utilize a control system having aninput-response relationship. A sensor generates a sensor signalrepresentative of a system parameter input (such as levels ofneurotransmitters), and provides the sensor signal to a controller. Thecontroller receives the sensor signal and generates commands that arecommunicated to the infusion formulation delivery device. The infusionformulation delivery device then delivers the infusion formulationoutput to the predetermined site at a determined rate and amount inorder to control the system parameter.

Sensor may comprise a sensor, sensor electrical components for providingpower to the sensor and generating the sensor signal, a sensorcommunication system for carrying the sensor signal to controller, and asensor housing for enclosing the electrical components and thecommunication system. Controller may include one or more programmableprocessors, logic circuits, or other hardware, firmware or softwarecomponents configured for implementing the control functions describedherein, a controller communication system for receiving the sensorsignal from the sensor, and a controller housing for enclosing thecontroller communication system and the one or more programmableprocessors, logic circuits, or other hardware, firmware or softwarecomponents. The infusion formulation delivery device may include asuitable infusion pump, infusion pump electrical components for poweringand activating the infusion pump, an infusion pump communication systemfor receiving commands from the controller, and an infusion pump housingfor enclosing the infusion pump, infusion pump electrical components,and infusion pump communication system. Such systems are described inU.S. Pat. No. 6,740,072, which is incorporated herein by reference inits entirety.

In certain embodiments, the sensor can be an electrode that senses ahyperactive burst pattern of activity or tonic firing, which in turnsstimulates the infusion pump to release a chemical or stimulating drugor agent to modify the neuronal activity. The chemical or stimulatingagent can be either an inhibiting agent or stimulating agent Herein,stimulating drugs comprise medications, anesthetic agents, synthetic ornatural peptides or hormones, neurotransmitters, cytokines and otherintracellular and intercellular chemical signals and messengers, otheragents such as zinc and the like. In addition, certainneurotransmitters, hormones, and other drugs are excitatory for sometissues, yet are inhibitory to other tissues. Therefore, where, herein,a drug is referred to as an “excitatory” drug, this means that the drugis acting in an excitatory manner, although it may act in an inhibitorymanner in other circumstances and/or locations. Similarly, where an“inhibitory” drug is mentioned, this drug is acting in an inhibitorymanner, although in other circumstances and/or locations, it may be an“excitatory” drug. In addition, stimulation of an area herein includesstimulation of cell bodies and axons in the area.

Similarly, excitatory neurotransmitter agonists (e.g., norepinephrine,epinephrine, glutamate, acetylcholine, serotonin, dopamine), agoniststhereof, and agents that act to increase levels of an excitatoryneurotransmitter(s) (e.g., edrophonium; Mestinon; trazodone; SSRIs(e.g., flouxetine, paroxetine, sertraline, citalopram and fluvoxamine);tricyclic antidepressants (e.g., imipramine, amitriptyline, doxepin,desipramine, trimipramine and nortriptyline), monoamine oxidaseinhibitors (e.g., phenelzine, tranylcypromine, isocarboxasid)),generally have an excitatory effect on neural tissue, while inhibitoryneurotransmitters (e.g., dopamine, glycine, and gamma-aminobutyric acid(GABA)), agonists thereof, and agents that act to increase levels of aninhibitory neurotransmitter(s) generally have an inhibitory effect(e.g., benzodiasepine (e.g., chlordiazepoxide, clonazepam, diazepam,lorazepam, oxazepam, prazepam alprazolam); flurazepam, temazepam, ortriazolam). (Dopamine acts as an excitatory neurotransmitter in somelocations and circumstances, and as an inhibitory neurotransmitter inother locations and circumstances). However, antagonists of inhibitoryneurotransmitters (e.g., bicuculline) and agents that act to decreaselevels of an inhibitory neurotransmitter(s) have been demonstrated toexcite neural tissue, leading to increased neural activity. Similarly,excitatory neurotransmitter antagonists (e.g., prazosin, and metoprolol)and agents that decrease levels of excitatory neurotransmitters mayinhibit neural activity. Yet further, lithium salts, anesthetics (e.g.,lidocane), and magnesium may also be used in combination with electricalstimulation.

VI. Treating Neurological Conditions

The present stimulation system and/or method acts to stimulate neuronaltissue which in turn stimulate the brain and cause/allow the brain toact in the best interest of the host through use of the brain's naturalmechanisms. The prior art fails to recognize that stimulation of atleast one the predetermined areas using the stimulation parameters ofthe present invention can provide the therapeutic treatments accordingto the instant invention.

Accordingly, the present invention relates to modulation of neuronalactivity to affect neurological, neuropsychological or neuropsychiatricactivity. The present invention finds particular application in themodulation of neuronal function or processing to affect a functionaloutcome. The modulation of neuronal function is particularly useful withregard to the prevention, treatment, or amelioration of neurological,psychiatric, psychological, conscious state, behavioral, mood, andthought activity (unless otherwise indicated these will be collectivelyreferred to herein as “neurological activity” which includes“psychological activity” or “psychiatric activity”). When referring to apathological or undesirable condition associated with the activity,reference may be made to a neurological disorder which includes“psychiatric disorder” or “psychological disorder” instead ofneurological activity or psychiatric or psychological activity. Althoughthe activity to be modulated usually manifests itself in the form of adisorder such as a attention or cognitive disorders (e.g., AutisticSpectrum Disorders); mood disorder (e.g., major depressive disorder,bipolar disorder, and dysthymic disorder) or an anxiety disorder (e.g.,panic disorder, posttraumatic stress disorder, obsessive-compulsivedisorder and phobic disorder); neurodegenerative diseases (e.g.,multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis(ALS), Parkinson's disease, Huntington's Disease, Guillain-Barresyndrome, myasthenia gravis, and chronic idiopathic demyelinatingdisease (CID)), movement disorders (e.g, dyskinesia, tremor, dystonia,chorea and ballism, tic syndromes, Tourette's Syndrome, myoclonus,drug-induced movement disorders, Wilson's Disease, ParoxysmalDyskinesias, Stiff Man Syndrome and Akinetic-Ridgid Syndromes andParkinsonism), epilepsy, tinnitus, pain, phantom pain, diabetesneuropathy, one skilled in the art appreciates that the invention mayalso find application in conjunction with enhancing or diminishing anyneurological or psychiatric function, not just an abnormality ordisorder. Neurological activity that may be modulated can include, butnot be limited to, normal functions such as alertness, conscious state,drive, fear, anger, anxiety, repetitive behavior, impulses, urges,obsessions, euphoria, sadness, and the fight or flight response, as wellas instability, vertigo, dizziness, fatigue, photofobia, concentrationdysfunction, memory disorders, headache, dizziness, irritability,fatigue, visual disturbances, sensitivity to noise (misophonia,hyperacusis, phonofobia), judgment problems, depression, symptoms oftraumatic brain injury (whether physical, emotional, social orchemical), autonomic functions, which includes sympathetic and/orparasympathetic functions (e.g., control of heart rate), somaticfunctions, and/or enteric functions. Thus, the present inventionencompasses modulation of central and/or peripheral nervous systems.

Other neurological disorders can include, but are not limited toheadaches, for example, migraine, trigeminal autonomic cephalgia(cluster headache (episodic and chronic)), paroxysmal hemicrania(epidsodic and chronic), hemicrania continua, SUNCT (shortlastingunilateral neuralgiform headache with conjunctival injection andtearing), cluster tic syndrome, trigenminal neuroalgia, tension typeheadache, idiopathic stabbing headache, etc. The neurostimulation devicecan be implanted intracranially or peripherally, for example, but notlimited to implanting a neurostimulation device occipitally for thetreatment of headaches.

Autonomic and/or enteric nervous system disorders that can be treatedusing the stimulation system and/or method of the present inventioninclude, but are not limited to hypertension, neurosis cordis or heartrhythm disorders, obesity, gastrointestinal motion disorders,respiratory disorders, diabetes, sleep disorders, snoring, incontinenceboth urologic and gastrointestinal, sexual dysfunction, chronic fatiguesyndrome, fibromyalgia, whiplash associated symptoms, post-concussionsyndrome, posttraumatic stress disorder etc.

Yet further immunological disorders may also be treated using thestimulation system and/or method of the present invention. This is basedon the fact that the immune system senses antigens coordinatesmetabolic, endocrine and behavioral changes that support the immunesystem and modulates the immune system via neuroendocrine regulation anddirect immune cell regulation. Such immunological disorders include,such as allergy, rhinitis, asthma, rheumatoid arthritis, psoriasisarthritis, lupus erythematosus disseminatus, multiple sclerosis andother demyelinating disorders, autoimmune thyroiditis, Crohn's disease,diabetis melitus etc.

Yet further tumoral disorders, both malignant and benign may also betreated using the stimulation system and/or method of the presentinvention. This is based on the fact that tumoral behavior is linked toimmunological function. This is seen in immunodeficiency syndromes suchas AIDS and hematological disorders, where multiple and different tumorsdevelop. In this setting neuromodulation could indirectly influencetumoral behavior.

Yet further neuroendocrine disorders may also be treated using thestimulation system and/or method of the present invention. Suchdisorders are stress reactions, hypothalamic-pituitary axis dysfunction,etc

Yet further functional disorders may also be treated using thestimulation system and/or method of the present invention. Suchdisorders can be anorexia, boulemia, phobias, addictions, paraphilia,psychosis, depression, bipolar disorder, kleptomania, aggression, orantisocial sexual behavior. One skilled in the art appreciates that theinvention may also find application in conjunction with enhancing ordiminishing any neurological or psychiatric function, not just anabnormality or disorder.

The present invention finds particular utility in its application tohuman neurological disorders, for example psychological or psychiatricactivity/disorder and/or physiological disorders. One skilled in the artappreciates that the present invention is applicable to other animalswhich exhibit behavior that is modulated by the neuronal tissue. Thismay include, for example, primates, canines, felines, horses, elephants,dolphins, etc. Utilizing the various embodiments of the presentinvention, one skilled in the art may be able to modulate neuronalfunctional outcome to achieve a desirable result.

One technique that offers the ability to affect neuronal function is thedelivery of electrical and/or chemical and/or magnetic stimulation forneuromodulation directly to target tissues or predetermined neuronalsites via an implanted device having a probe. The probe can bestimulation lead or electrode assembly. The electrode assembly may beone electrode, multiple electrodes, or an array of electrodes in oraround the target area. The proximal end of the probe is coupled to asystem to operate the device to stimulate the target site. Thus, theprobe is coupled to an electrical signal source, which, in turn, isoperated to stimulate the target tissue or predetermined site.

A predetermined site is a neuronal tissue, which can include eitherperipheral neuronal tissue and/or central neuronal tissue. Neuronaltissue includes any tissue associated with the peripheral nervous systemor the central nervous system. Peripheral neuronal tissue can include anerve root or root ganglion or any neuronal tissue that lies outside thebrain, brainstem or spinal cord. Central neuronal tissue includes braintissue, spinal tissue or brainstem tissue.

Peripheral nerves can include, but are not limited to olfactory nerve,optic, nerve, oculomotor nerve, trochlear nerve, trigeminal nerve,abducens nerve, facial nerve, vestibulocochlear (auditory) nerve,glossopharyngeal nerve, vagal nerve, accessory nerve, hypoglossal nerve,suboccipital nerve, the greater occipital nerve, the lesser occipitalnerve, the greater auricular nerve, the lesser auricular nerve, thephrenic nerve, brachial plexus, radial axillary nerves, musculocutaneousnerves, radial nerves, ulnar nerves, median nerves, intercostal nerves,lumbosacral plexus, sciatic nerves, common peroneal nerve, tibialnerves, sural nerves, femoral nerves, gluteal nerves, thoracic spinalnerves, obturator nerves, digital nerves, pudendal nerves, plantarnerves, saphenous nerves, ilioinguinal nerves, gentofemoral nerves, andiliohypogastric nerves. Also all sympathetic and parasympathetic nervesand all sympathetic and parasympathetic parts of peripheral nerves.

Brain tissue can include thalamus/sub-thalamus (all thalamic nuclei,inclusive of medial and lateral geniculate body, intralaminar nuclei,nucleus reticularis, pulvinar, etc) basal ganglia (inclusive of putamen,caudate nucleus, globus pallidus), hippocampus, amygdala, hypothalamus,epithalamus, mammilary bodies, substantia nigra or cortex or whitematter tracts afferent to or efferent from the abovementioned braintissue, inclusive of the corpus callosum, formix, internal capsula,anterior and posterior commissural, cerebral peduncles etc. Brain tissuealso includes cerebellum, inclusive of cerebellar peduncles, andcerebeller nuclei such as fastigial nucleus, globose nucleus, dentatenucleus, emboliform nucleus. Brain tissue also includes auditory cortexand the somatosensory cortex.

Spinal tissue can include the ascending and descending tracts of thespinal cord, more specifically, the ascending tracts of that compriseintralaminar neurons or the dorsal column, fsciculus gracilis andcuneatus, dorsolateral fasciculus of Lissauer, spinocerebellar andcerebellospinal tracti, spinothalamic, spinoolivary, spinotectal andspinoreticular tracti. Also inclusive are the rubrospinal,reticulospinal, vestibulospinal, tectospinal and corticospinal tractiand the medial longitudinal fasciculus etc. Any area of the spinal cordmay be stimulated in the present invention for example the any neuronaltissue associated with any of the cervical vertebral segments (C1, C2,C3, C4, C5, C6, C7) and/or any tissue associated with any of thethoracic vertebral segments (T1, T2, T3, T4, T5, T6, T7, T8, T9, T10,T11, 12) and/or any tissue associated with any of the lumbar vertebralsegments (L1, L2, L3, L4. L5, L6) and/or any tissue associated with thesacral vertebral segments (S1, S2, S3, S4, S5).

The brainstem tissue can include the medulla oblongata, pons ormesencephalon, more particular the posterior pons or posteriormesencephalon, Lushka's foramen, and ventrolateral part of the medullaoblongata inclusive of the cranial nerve nuclei, the reticular formatio,substantia nigra, red nucleus, the periaquaductal grey. This is alsoinclusive of white matter tracts such as the medial longitudinalfasciculus, lemniscus medialis, trigeminalis, spinalis and lateralis andsinothalamic, spinocerebellar, corticospinal and corticonuclear tracti,etc.

Using the stimulation system of the present invention, the predeterminedsite or target area is stimulated in an effective amount or effectivetreatment regimen to decrease, reduce, modulate or abrogate theneurological disorder. Thus, a subject is administered a therapeuticallyeffective stimulation so that the subject has an improvement in theparameters relating to the neurological disorder or condition includingsubjective measures such as, for example, neurological examinations andneuropsychological tests (e.g., Minnesota Multiphasic PersonalityInventory, Beck Depression Inventory, Mini-Mental Status Examination(MMSE), Hamilton Rating Scale for Depression, Wisconsin Card SortingTest (WCST), Tower of London, Stroop task, MADRAS, CGI, N-BAC, orYale-Brown Obsessive Compulsive score (Y-BOCS)), motor examination, andcranial nerve examination, and objective measures including use ofadditional psychiatric medications, such as anti-depressants, or otheralterations in cerebral blood flow or metabolism and/or neurochemistry.

Patient outcomes may also be tested by health-related quality of life(HRQL) measures: Patient outcome measures that extend beyond traditionalmeasures of mortality and morbidity, to include such dimensions asphysiology, function, social activity, cognition, emotion, sleep andrest, energy and vitality, health perception, and general lifesatisfaction. (Some of these are also known as health status, functionalstatus, or quality of life measures).

Treatment regimens may vary as well, and often depend on the health andage of the patient. Obviously, certain types of disease will requiremore aggressive treatment, while at the same time, certain patientscannot tolerate more taxing regimens. The clinician will be best suitedto make such decisions based on the known subject's history.

For purposes of this invention, beneficial or desired clinical resultsinclude, but are not limited to, alleviation of symptoms, improvement ofsymptoms, diminishment of extent of disease, stabilized (i.e., notworsening) state of disease, delay or slowing of disease progression,amelioration or palliation of the disease state, and remission (whetherpartial or total), whether objective or subjective. The improvement isany observable or measurable improvement. Thus, one of skill in the artrealizes that a treatment may improve the patient condition, but may notbe a complete cure of the disease.

In certain embodiments, in connection with improvement in one or more ofthe above or other neurological disorders, the electrical stimulationmay have a “brightening” effect on the person such that the person looksbetter, feels better, moves better, thinks better, and otherwiseexperiences an overall improvement in quality of life.

In certain embodiments, it is envisioned that the present inventionprovides at least one burst stimulus (e.g., electrical, chemical,magnetic and/or thermal) to a predetermined neuronal tissue site wherebythe stimulus alters neuronal activity thereby treating the disorder orcondition. The burst stimulus comprises a frequency in the range ofabout 1 Hz to about 300 Hz, more particular, in the range of about 1 Hzto about 12 Hz, and more particularly, in the range of about 1 Hz toabout 4 Hz, 4 Hz to about 7 Hz or about 8 Hz to about 12 Hz, 18 Hz to 20Hz, and 40 Hz. The burst stimulus comprises at least two spikes, forexample, each burst stimulus can comprise about 2 to about 100 spikes,more particularly, about 2 to about 10 spikes. Each spike can comprise afrequency in the range of about 1 Hz to about 1000 Hz, moreparticularly, in the range of about 50 to about 200 Hz or in the rangeof about 200 Hz to about 500 Hz. Those of skill in the art understandthat the frequency for each spike within a burst can vary. Yet further,the spike interval can also vary from about 0.5 milliseconds to about100 milliseconds.

In further embodiments, the burst stimulus is followed by an inter-burstinterval. The inter-burst interval has duration in the range of about 5milliseconds to about 5 seconds, more preferably, about 10 millisecondsto about 300 milliseconds. It is envisioned that the burst stimulus hasa duration in the range of about 10 milliseconds to about 5 seconds,more particular, in the range of about 250 msec to 1000 msec (1-4 Hzburst firing), 145 msec to about 250 msec (4-7 Hz), 145 msec to about 80msec (8-12 Hz) or 1 to 5 seconds in plateau potential firing. The burststimulus and the inter-burst interval can have a regular pattern or anirregular pattern (e.g., random or irregular harmonics).

In further embodiments, the stimulation system of the present inventioncan incorporate an infusion or drug delivery device. The device cancontain a sensor, for example an electrode, that senses a hyperactiveburst pattern of activity, which in turns stimulates the infusion pumpto release a chemical or stimulating drug or agent to modify theneuronal activity. The chemical or stimulating agent can be either aninhibiting agent or stimulating agent, as described above.

In addition to electrical stimulation and/or chemical stimulation, otherforms of stimulation can be used, for example magnetic, or thermal orcombinations thereof. Magnetic stimulation can be provided by internallyimplanted probes or by externally applied directed magnetic fields, forexample, U.S. Pat. Nos. 6,592,509; 6,132,361; 5,752,911; and 6,425,852,each of which is incorporated herein in its entirety. Thermalstimulation can be provided by using implanted probes that are regulatedfor heat and/or cold temperatures which can stimulate or inhibitneuronal activity, for example, U.S. Pat. No. 6,567,696, which isincorporated herein by reference in its entirety.

The neuromodulation method of the present invention can be used to altera physiological and/or pathological signaling pattern. Thus, it isenvisioned that the stimulation method as used herein can alter suchpatterns to alleviate the neurological condition or disease, or toimprove or enhance a desired physiological function (e.g., selfconfidence, alleviating shyness, distrust etc).

In certain embodiments, the neuromodulation method can be used to treatneurological disorders or diseases that result from incorrect centralnervous system control in which the disorder comprises a regularbursting rhythm. Such disorders having a regular bursting rhythminclude, but are not limited to Parkinson's, epilepsy, tinnitus andphantom pain or other forms of deafferentation or central pain. Thus, itis envisioned that the neuromodulation of the present invention willalter or disrupt the regular bursting rhythm associated with thedisorder.

In further embodiments, it is envisioned that other central neuronaltissue may be stimulated, for example, tissue associated with the spinalcord, more specially the dorsal horn or column to treat any neurologicalcondition or disorder associated with innervations from such, forexample, pain. It is known that deafferented dorsal horn cells fire in aburst mode firing (Guenot 2003), which namely adding a valence to thehigh frequency tonic information (Jeanmonod 1989; Swadlow 2001, Sherman2001). Thus, the present invention can modulate or disrupt the burstmode firing of the dorsal horn in such conditions thereby treating thecondition.

Still further, it is contemplated that the neuromodulation system of thepresent invention can be used to alter the firing mode for predeterminedperipheral neuronal tissue. For example, it is known that brief burststhat come from the periphery can more reliably transmit neuralinformation between primary afferent fibers and spinal dorsal hornneurons (Wan 2004). One of the reasons might be that in contrast totonic firing (both low frequency—1 Hz—or high frequency—100 Hz), burstfiring releases BDNF (brain derived neurotrophic factor) from dorsalhorn cells (Lever 2001), which is known to be part of a generalmechanism for activity-dependent modification of synapses in thedeveloping and adult nervous system. Thus, diseases of abnormal trophicsupport (such as neurodegenerative diseases) and diseases of abnormalexcitability (such as epilepsy and central pain sensitization) can berelated in some cases to abnormal BDNF signaling (Binder 2004). As such,it is envisioned that stimulation of peripheral neuronal tissue usingthe stimulation parameters or neuromodulation system of the presentinvention will alter, override, or disrupt the burst firing, thusaltering release of BDNF, thereby treating the neurological condition ordisorder.

Still further, it is known that the sympathetic system fires in bursts,and the parasympathetic system as well. Any neurological ornon-neurological disorder associated with a hypoactive, hyperactive ormaladaptive sympathetic or parasympathetic firing can be modified usingthis method.

Still further, the neuromodulation method of the present invention canbe used to treat neurological disorders or diseases that result fromincorrect central nervous system control in which the disorder comprisesan irregular bursting rhythm. Such disorders can include, but are notlimited to dystonia or chorea or hallucinations. Thus, it is envisionedthat such conditions are caused or linked to arrhythmic burst firing ordesynchronized tonic firing can be treated utilizing the neuromodulationsystem or stimulation parameters of the present invention.

In different motor, sensory and autonomic neurological disorders twomechanisms might be involved: the firing rate is altered in tonic andburst firing cells and the amount of burst firing is increased. A secondmechanism involved is an alteration in the synchrony of neuronal firing,which is often increased.

Thus, burst firing neuromodulation is indicated for modifying bothphysiological or abnormal tonic and burst firing in the brain,brainstem, spinal cord and peripheral nervous system, inclusive of theautonomic system. This type of neuromodulation can be modify burstfiring patterns, but also for tonic firing patterns

A. Sensory Disorders

1. Tinnitus

In the auditory system, tonic firing transmits the contents of auditoryinformation, while burst firing transmit the valence or importanceattached to that sound (Lisman 1997; Sherman 2001; Swadlow and Gusev2001). Repetitive stimulus presentation results in decreased neuronalresponse to that stimulus, known as auditory habituation at the singlecell level (Ulanovsky et al., 2003), auditory mismatch negativity atmultiple cell level (Naatanen et al., 1993; Ulanovsky et al., 2003).

Tinnitus is a noise in the ears, often described as ringing, buzzing,roaring, or clicking. Subjective and objective forms of tinnitus exist,with objective tinnitus often caused by muscle contractions or otherinternal noise sources in the area proximal to auditory structures. Incertain cases, external observers can hear the sound generated by theinternal source of objective tinnitus. In subjective forms, tinnitus isaudible only to the subject. Tinnitus varies in perceived amplitude,with some subjects reporting barely audible forms and others essentiallydeaf to external sounds and/or incapacitated by the intensity of theperceived noise.

Tinnitus is usually constantly present, e.g., a non-rational valence isattached to the internally generated sound, and there is no auditoryhabituation to this specific sound, at this specific frequency. Thus,tinnitus is the result of hyperactivity of lesion-edge frequencies, andauditory mismatch negativity in tinnitus patients is specific forfrequencies located at the audiometrically normal lesion edge (Weisz2004).

As pathological valence of the tinnitus sound is mediated by burstfiring, burst firing is increased in tinnitus in the extralemniscalsystem (Chen and Jastreboff 1995; Eggermont and Kenmochi 1998; Eggermont2003), in the inner hair cells (Puel 1995; Puel et al., 2002), theauditory nerve (Moller 1984), the dorsal and external inferiorcolliculus (Chen and Jastreboff 1995), the thalamus (Jeanmonod, Magninet al., 1996) and the secondary auditory cortex (Eggermont and Kenmochi1998; Eggermont 2003). Furthermore, quinine, known to generate tinnitus,induces an increased regularity in burst firing, at the level of theauditory cortex, inferior colliculus and frontal cortex (Gopal and Gross2004). It is contemplated that tinnitus can only become conscious if anincreased tonic firing rate is present in the lemniscal system,generating the sound. This increased firing activity has beendemonstrated in the lemniscal dorsal cochlear nucleus (Kaltenbach,Godfrey et al., 1998; Zhang and Kaltenbach 1998; Kaltenbach and Afman2000; Brozoski, Bauer et al., 2002; Zacharek et al., 2002; Kaltenbach etal., 2004), inferior colliculus (Jastreboff and Sasaki 1986; Jastreboff,Brennan et al., 1988; Jastreboff 1990) (Gerken 1996) and primaryauditory cortex (Komiya, 2000). Interestingly, not only tonic firing isincreased generating the tinnitus sound, but also the burst firing (Ochiand Eggermont 1997) (keeping it conscious) at a regular basis.Repetitive burst firing is known to generate tonic gamma band activity(Gray and Singer 1989; Brumberg, 2000). Thus, it is envisioned that thepresent invention can be used to modify burst firing, thus modifyingtonic gamma activity.

Burst mode firing boosts the gain of neural signaling of important ornovel events by enhancing transmitter release and enhancing dendriticdepolarization, thereby increasing synaptic potentiation. Conversely,single spiking mode may be used to dampen neuronal signaling and may beassociated with habituation to unimportant events (Cooper 2002). It isbelieved that the main problem in tinnitus is that the internallygenerated stimulus does not decay due to the presence of regularbursting activity telling the cortex this signal is important and has toremain conscious.

Thus, in the present invention, it is envisioned that theneuromodulation system can attack either of these two pathways: slowingdown tonic firing in the lemniscal system (below 40 Hz) or removing thevalence attached to it by the extralemniscal system by suppressing theregular bursting rhythm, thereby treating tinnitus. Yet further, theneuromodulation system of the present invention can also make thetinnitus disappear via auditory habituation. Suppressing the rhythmicburst firing in the frontal cortex may alter the emotional affect givento the tinnitus, with the tinnitus persisting, a situation known by manypeople perceiving tinnitus, but without much influence on their dailylife. Such methods of treating tinnitus are further described in U.S.Provisional Applications entitled “Deep Brain Stimulation to TreatTinnitus” filed Oct. 21, 2004; “Peripheral Nerve Stimulation to TreatTinnitus” filed Oct. 21, 2004; and “Dorsal Column Stimulation to TreatTinnitus” filed Oct. 21, 2004, each of which is incorporated byreference in its entirety.

2. Phantom Pain

In phantom pain the same is noted as in Parkinson's Disease (PD) andtinnitus. In humans, the tonic firing rate increases (Yamashiro et al.,2003), as well as the amount of burst firing in the deafferentedreceptive fields (Rinaldi et al., 1991; Jeanmonod et al., 1996;Radhakrishnan et al., 1999) in the somatosensory thalamic nuclei(Rinaldi et al., 1991; Lenz et al., 1998), as well as activity in the inthe intralaminar nuclei (Weigel and Krauss 2004). Synchrony in firing isalso increased. This is similar to what is seen in animal neuropathicpain models (Lombard and Besson 1989; Nakamura and Atsuta 2004)(Yamashiro et al., 1991). These results suggest that in pain decreasedspike frequency adaptation and increased excitability develops afterinjury to sensory neurons. Through decreased Ca²⁺ influx, the cellbecomes less stable and more likely to initiate or transmit bursts ofaction potentials (McCallum et al., 2003).

Thus, it is envisioned that that the neuromodulation system or method ofthe present invention will alter or disrupt the regular bursting rhythmassociated with the phantom pain.

3. Motor Disorders

In Parkinson's disease (PD), the striatum is viewed as the principalinput structure of the basal ganglia, while the internal pallidalsegment (GPi) and the substantia nigra pars reticulata (SNr) are outputstructures. Input and output structures are linked via a monosynaptic“direct” pathway and a polysynaptic “indirect” pathway involving theexternal pallidal segment (GPe) and the subthalamic nucleus (STN).According to current schemes, striatal dopamine (DA) enhancestransmission along the direct pathway (via D1 receptors), and reducestransmission over the indirect pathway (via D2 receptors) (Wichmann andDeLong 2003).

Increased firing rates are noted in PD, both in the globus pallidus(Magnin et al., 2000) and the subthalamic nucleus (Levy et al., 2002)and is reversed in successful STN stimulation in PD (Welter et al.,2004; Boraud et al., 1996). Synchronization between firing rates isimportant: lower frequency oscillations facilitate slow idling rhythmsin the motor areas of the cortex, whereas synchronization at highfrequency restores dynamic task-related cortical ensemble activity inthe gamma band (Brown 2003). In PD, a (hyper)synchronization is relatedto tremor (Levy et al., 2002), similarly to what is seen in the animalParkinson model (Raz et al., 2000; Nini et al., 1995).

Two or more firing modes exist in the subthalamic nucleus: tonic firing(68%), phasic or burst firing (25%) and phasic-tonic (7%)(Magarinos-Ascone et al., 2002).

In the monkey MPTP Parkinson model, burst firing, which occurs at 4 to 8Hz, increases in the STN and Gpi in comparison to normal firing (from69% and 78% in STN and GPi to 79% and 89%, respectively) (Bergman etal., 1994), as well as burst duration, without increase in the amount ofspikes per burst (Bergman et al., 1994). Abnormally increased tonic andphasic activity in STN leads to abnormal GPi activity and is a majorfactor in the development of parkinsonian motor signs (Wichmann et al.,1994). The percentage of cells with 4- to 8-Hz periodic activitycorrelates with tremor and is significantly increased from 2% to 16% inSTN and from 0.6% to 25% in GPi with the MPTP treatment (Bergman et al.,1994). These cells are also recorded in humans with PD (Hutchison etal., 1997). Furthermore, synchronization increases, e.g., a decrease inindependent activity (Raz et al., 2000; Nini et al., 1995), both intonically firing cells (Raz et al., 2001) and burst firing cells. Thus,it is envisioned that that the neuromodulation or stimulation system ormethod of the present invention will alter or disrupt or override theregular bursting rhythm associated with PD.

Other movement disorders, for example, chorea, Huntington's chorea,hemiballism and parkinsonian tremor all differ in the amount ofregularity in their muscle contractions. (Hashimoto and Yanagisawa1994). The regularities of interval, amplitude, rise time, and EMGactivity differs within order of regularity, such PD, vascular chorea,Huntington chorea and hemiballism being least regular (Hashimoto andYanagisawa 1994). However, in chorea (Hashimoto et al., 2001),hemiballism (Postuma and Lang 2003) and Huntington's disease (Cubo etal., 2000), the firing rate might be decreased in contrast to PD. Burstdischarges are, however, correlated to the choreatic movements (Kanazawaet al., 1990), similarly to what is noted in PD (Bergman, Wichmann etal., 1994). Thus, the neuromodulation system and/or method of thepresent invention is used to alter or disrupt the dysfunctional firingrate of the disease or condition.

B. Autonomic Disorders

The autonomic nervous system (ANS) is predominantly an efferent systemtransmitting impulses from the central nervous system (CNS) toperipheral organ systems. Its effects include control of heart rate andforce of contraction, constriction and dilatation of blood vessels,contraction and relaxation of smooth muscle in various organs, visualaccommodation, pupillary size and secretions from exocrine and endocrineglands. In addition to it being predominantly an efferent system, thereare some afferent autonomic fibers (e.g., transmit information from theperiphery to the CNS), which are concerned with the mediation ofvisceral sensation and the regulation of vasomotor and respiratoryreflexes, for example the baroreceptors and chemoreceptors in thecarotid sinus and aortic arch which are important in the control ofheart rate, blood pressure and respiratory activity. These afferentfibers are usually carried to the CNS by major autonomic nerves such asthe vagus, splanchnic or pelvic nerves, although afferent pain fibersfrom blood vessels may be carried by somatic nerves.

The ANS is divided into two separate divisions, the parasympathetic andsympathetic systems. This division is based on anatomical and functionaldifferences. Both of these systems consist of myelinated preganglionicfibres that make synaptic connections with unmyelinated postganglionicfibres, and it is these which then innervate the effector organ. Thesesynapses usually occur in clusters called ganglia. Most organs areinnervated by fibers from both divisions of the ANS, and the influenceis usually opposing (e.g., the vagus slows the heart, whilst thesympathetic nerves increase its rate and contractility), although it maybe parallel (e.g., the salivary glands).

The activity recorded from mammalian sympathetic nerves comes in bursts,which result from large numbers of fibers firing synchronously. Humansympathetic nerve activity behaves similarly. Vasomotor, cardiac andsudomotor nerve fibers all fire in bursts. Bursts in post-ganglionicnerves are driven by synchronously firing preganglionic neurons. Burstamplitude, which reflects the number of fibers firing together, andburst probability are controlled independently (McAllen and Malpas1997). The sympathetic nerve also fires in a 10 Hz tonic mode (Barman,Kitchens et al., 1997). This 10-Hz rhythm is also involved incardiovascular regulation, as blood pressure falls significantly whenthe 10-Hz rhythm is eliminated. Cardiac-related burst activity and 10-Hzrhythms are generated by different pools of brainstem neurons (Barman,Kitchens et al., 1997).

When electrical stimulation is applied to the sympathetic nerve, burststimulation is more powerful (vasoconstrictor) than tonic mode. Theamount of spikes per burst also determines the efficacy of stimulation(Ando, Imaizumi et al., 1993). The same is seen with electricalstimulation of the cervical sympathetic nerve trunk delivered at 50 Hzin bursts of 1 s every 10 s. Burst stimulation evoked a more copious,uniform and reproducible flow of saliva than when delivered at 10 Hzcontinuously (Anderson, Garrett et al., 1988). Similar superior resultswith burst stimulation have been obtained studying nasal mucosareactivity: both types of stimulation reduced nasal blood flow andvolume, but the responses were significantly larger with burststimulation at 0.59 Hz compared to tonic 0.59 Hz stimulation (Lacroix,Stjarne et al., 1988).

In the parasympathetic system, burst firing and tonic firing co-exist.For example, one population of neurons responds with a brief burst ofaction potentials at the onset of the depolarization, accommodating tothe stimulus, and the other population responds with repetitive actionpotentials persisting throughout the duration of the stimulus, notaccommodating to the stimulus (Myers 1998; Bertrand 2004).

Burst stimulation at 0.1 Hz with 20 Hz spiking of the parasympatheticnerve results in a 200-fold more powerful enzyme induction than 2 Hztonic stimulation, when delivering the same amount of pulses (in thesublingual gland) (Nilsson, Rosengren et al., 1991).

1. Hypertension and Heart Rhythm Disorders

The nucleus of the solitary tract (NTS), a termination site for primaryafferent fibers from baroreceptors and other peripheral cardiovascularreceptors, and the paratrigeminal nucleus (Pa5) contain bloodpressure-sensitive neurons, some of which have rhythmic activity lockedto the cardiac cycle, making them key components of the central pathwayfor cardiovascular regulation. NTS and Pa5 baroreceptor-activatedneurons possess phasic discharge patterns locked to the cardiac cycle(Junior, Caous et al., 2004). The human insular cortex is involved incardiac regulation. The left insula is predominantly responsible forparasympathetic cardiovascular effects. On stimulation of the leftinsular cortex, parasympathetic tone increases resulting in bradycardiaand depressor responses more frequently than tachycardia and pressoreffects (p<0.005) (Oppenheimer, Gelb et al., 1992). The converse appliesfor the right insular cortex: stimulation of the human right insulaincreases sympathetic cardiovascular tone (Oppenheimer 1993). Acute leftinsular stroke increases basal cardiac sympathetic tone and isassociated with a decrease in randomness of heart rate variability(Oppenheimer, Kedem et al., 1996). Increased sympathoadrenal tone,resulting from damage to cortical areas involved in cardiac andautonomic control can induce cardiac damage by nonischemic mechanisms(Oppenheimer and Hachinski 1992).

Brain noradrenaline (NA) neurons in the locus coeruleus (LC) and majorparts of the SNS respond by burst activation in concert to stressfulstimuli implying novelty or fear. (Svensson 1987). In hypertension,burst firing is increased (Schlaich, Lambert et al., 2004) (Ester,Rumantir et al., 2001).

The autonomic nervous system plays an important role in the genesis ofvarious cardiac rhythm disorders. In patients with paroxysmal atrialfibrillation, it is important to distinguish vagally mediated fromadrenergically mediated atrial fibrillation. The former is considered torepresent a form of lone atrial fibrillation affecting particularlymales aged 40 to 50 years. The arrhythmic episodes manifest themselvesmost often during the night lasting from minutes to hours, whereas inadrenergic mediated atrial fibrillation, atrial fibrillation is oftenprovoked by emotional or physical stress. (Hohnloser, van de Loo et al.,1994)

Thus, hypertension (e.g., neurogenic hypertension) can be treated withburst stimulation of the left insula using the stimulation system of thepresent invention. In a similar fashion, bradycardia can be treated byburst stimulation of the right insula as subjects with bradycardia havesignificantly higher metabolic activity in the right (p<0.0001) and inthe left temporal insula (p<0.015) than those with normal heart rates(Volkow, Wang et al., 2000). Lone atrial fibrillation can be treated byeither by left or rightsided burst stimulation depending on whether itis vagally or adrenergicly induced.

2. Sleep Apnea

Activity in the sympathetic nervous system is enhanced not only inobstructive apnea, but also in central and mixed apnea (Shimizu,Takahashi et al., 1997). Burst rate during apnea is higher in centralapneas than in obstructive apneas. Burst rate is the central componentof mixed apnea and the obstructive component of mixed apneas (Shimizu,Takahashi et al., 1997).

This intense sympathoexcitation is due to chronic or intermittenthypoxia (Cutler, Swift et al., 2004; Cutler, Swift et al., 2004).Pathological sympathoexcitation appears to depend on both recruitmentand increased burst firing frequency. In OSAS, also the amount of spikesper burst is increased, (Elam, McKenzie et al., 2002) and at night,arousal-induced reduction in sympathetic burst latency is noted (Xie,Skatrud et al., 1999).

Functional MRI or FMRI studies demonstrate reduced neural signals withinthe frontal cortex, anterior cingulate, cerebellar dentate nucleus,dorsal pons, anterior insula and lentiform nuclei. Signal increases inOSA over control subjects are seen in the dorsal midbrain, hippocampus,quadrangular cerebellar lobule, ventral midbrain and ventral pons(Macey, Macey et al., 2003). In the rat, the respiratory area in theanterior insular cortex consist of two distinct zones which overlap aregion modulating the gastrointestinal activity (Aleksandrov,Aleksandrova et al., 2000). In the more rostral area, there is adecrease in respiratory airflow and tidal volume with no alteration ofthe respiratory rate (the inhibition response), and in the other thereis an increase in respiratory rate and inspiratory airflow (theexcitation response).

Thus, the present invention can be used to activate respiration duringapneas by burst stimulation of the anterior insula.

C. Obesity

Food presentation in normal healthy, non-obese individuals significantlyincreases metabolism in the whole brain (24%, P<0.01), and these changesare largest in superior temporal, anterior insula, and orbitofrontalcortices (Wang, Volkow et al., 2004). Food-related visual stimuli elicitgreater responses in the amygdala, parahippocampal gyrus and anteriorfusiform gyrus when participants are in a hungry state relative to asatiated state (LaBar, Gitelman et al., 2001). Hunger is associated withsignificantly increased rCBF in the vicinity of the hypothalamus andinsular cortex and in additional paralimbic and limbic areas(orbitofrontal cortex, anterior cingulate cortex, and parahippocampaland hippocampal formation), thalamus, caudate, precuneus, putamen, andcerebellum (Tataranni, Gautier et al., 1999). Satiation is associatedwith increased rCBF in the vicinity of the ventromedial prefrontalcortex, dorsolateral prefrontal cortex, and inferior parietal lobule(Tataranni, Gautier et al. 1999). High-calorie foods yield significantactivation within the medial and dorsolateral prefrontal cortex,thalamus, hypothalamus, corpus callosum, and cerebellum. Low-caloriefoods yield smaller regions of focal activation within medialorbitofrontal cortex, primary gustatory/somatosensory cortex, andsuperior, middle, and medial temporal regions (Killgore, Young et al.,2003). Activity within the temporo-insular cortex in normal appetitivefunction is associated with the desirability or valence of food stimuli,prior to ingestion (Gordon, Dougherty et al., 2000). When a food iseaten to satiety, its reward value decreases. Responses of gustatoryneurons in the secondary taste area within the orbitofrontal cortex aremodulated by hunger and satiety, in that they stop responding to thetaste of a food on which an animal has been fed to behavioral satiation,yet may continue to respond to the taste of other foods (Critchley andRolls 1996; O'Doherty, Rolls et al., 2000). In the OFC, the rCBFdecreases in the medial OFC and increases in the lateral OFC as thereward value of food changes from pleasant to aversive for non-liquid(Small, Zatorre et al., 2001) and liquid foods (Kringelbach, O'Dohertyet al., 2003). In the insular gustatory cortex, neuronal responses togustatory stimuli are not influenced by the normal transition fromhunger to satiety. This is in contrast to the responses of a populationof neurons recorded in the hypothalamus, which only respond to the tasteof food when the monkey is hungry (Yaxley, Rolls et al., 1988). Brainresponses to hunger/satiation in the hypothalamus, limbic/paralimbicareas (commonly associated with the regulation of emotion), andprefrontal cortex (thought to be involved in the inhibition ofinappropriate response tendencies) might be different in obese and leanindividuals (Del Parigi, Gautier et al., 2002). Compared with leanwomen, obese women have significantly greater increases in rCBF in theventral prefrontal cortex and have significantly greater decreases inthe paralimbic areas and in areas of the frontal and temporal cortex(Gautier, Del Parigi et al., 2001). In obese women, the rCBF is higherin the right parietal and temporal cortices during the food exposurethan in the control condition. In addition, in obese women theactivation of the right parietal cortex is associated with an enhancedfeeling of hunger when looking at food (Karhunen, Lappalainen et al.,1997). This significantly higher metabolic activity in the bilateralparietal somatosensory cortex is noted in the regions where sensation tothe mouth, lips and tongue are located. The enhanced activity insomatosensory regions involved with sensory processing of food in theobese subjects can make them more sensitive to the rewarding propertiesof food related to palatability and can be one of the variablescontributing to their excess food consumption (Wang, Volkow et al.,2002).

Based on the abovementioned model, the stimulation system and/or methodof the present invention can be used to produce burst stimulation of the-orbitofrontal cortex or -insula to treat obesity especially in thosepeople who are constant eaters rather than binge or high volume eaters.Other targets that can be stimulated are the dorsolateral prefrontalcortex, thalamus, hypothalamus, corpus callosum, and cerebellum, as wellas the medial orbitofrontal cortex, primary gustatory/somatosensorycortex, and superior, middle, and medial temporal regions and theamygdalohippocampal area and anterior cingulated area.

D. Cognitive and Psychological Disorders

1. Depression

In patients suffering from a depression, a hypometabolism andhypoperfusion localized to the left middorsolateral frontal cortex(MDLFC) is noted (Baxter, Schwartz et al., 1989; Brody, Saxena et al.,2001). Furthermore decreased neural activity in the MDLFC, aka thedorsolateral prefrontal cortex, is correlated with severity ofdepression (Bench, Friston et al., 1992; Bench, Friston et al., 1993;Dolan, Bench et al., 1994) and is reversed upon recovery from depression(Bench, Frackowiak et al., 1995). Electroencephalography demonstratesincreased alpha power. Alpha power is thought to be inversely related toneural activity in left frontal regions of the brains of depressedpatients (Bruder, Fong et al., 1997).

Metabolic activity in the ventral perigenual ACC is increased indepressed patients relative to control subjects (Videbech, Ravnkilde etal., 2001) and is positively correlated with severity of depression(Drevets 1999). Furthermore, neural activity in this region decreases inresponse to antidepressant treatment (Brody, Saxena et al., 2001).

The MDLFC occupies the middle frontal and superior frontal gyri andcomprises cytoarchitectonic areas 46 and 9/46 (middle frontal gyrus) andarea 9 (superior frontal gyrus) (Paus and Barrett 2004). The MDLFC hasconnections with sensory areas processing visual (prestriate andinferior temporal cortices), auditory (superior temporal cortex) andsomatosensory (parietal cortex) information (Petrides and Pandya 1999).The MDLFC also reciprocally connects with the anterior and, to a lesserextent, posterior cingulate cortices (Bates and Goldman-Rakic 1993).

Transcranial magnetic stimulation has been performed in the treatment ofdepression. The left MDLFC is the most common target for rTMS treatmentof depression (Paus and Barrett 2004), and rTMS of the left MDLFCmodulates the blood-flow response in the ACC (Barrett, Della-Maggiore etal., 2004; Paus and Barrett 2004). High-frequency (20 Hz) andlow-frequency (1 Hz) stimulation seem to have an opposite effect.High-frequency stimulation (HFS) increases and low-frequency stimulation(LFS) decreases cerebral blood flow (CBF) and/or glucose metabolism inthe frontal cortex and other linked brain regions (Speer, Kimbrell etal., 2000; Kimbrell, Little et al., 1999; and Post, Kimbrell et al.,1999).

Successful treatment of depression with TMS results in normalization ofhypoperfusion (with HFS) and normalization hyperperfusion (with LFS)(Kimbrell, Little et al., 1999). Thus, TMS treatment for depression canbe proposed using 20 Hz left frontal cortex (Kimbrell, Little et al.,1999; Paus and Barrett 2004) or 1 Hz right frontal cortex (Klein,Kreinin et al., 1999).

In the ACC of the rat, three kinds of burst firing is recorded. Rhythmicburst firing with inter-burst intervals of 80 and 200 ms and nonrhythmic burst firing (Gemmell, Anderson et al., 2002). ACC stimulationsevoke both tonic and burst reactions in the dorsolateral prefrontalcortex (Desiraju 1976). Similarly to other cortical areas, thedorsolateral prefrontal cortex has burst firing cells, tonic firingcells and mixed firing cells. Similarly to other areas, the burst firingnotices new incoming sensory (auditory, visual) information, and tonicfiring continues as long as the stimulus lasts (Ito 1982). TMS in burstmode is more powerful than TMS in tonic mode. For example, 20 seconds of5 Hz burst firing with 3 pulses at 50 Hz per burst have the same effectas 10 minutes 1 Hz tonic TMS.

Thus, the present stimulation system and/or method can be used to treatdepression. For example, a cortical electrode is implanted on the rightMDLFC and a 5 Hz burst mode is used to treat recurring depressions thatreact to a test stimulation with TMS.

2. Obsessive Convulsive Disorder

Obsessive-compulsive disorder is a worldwide psychiatric disorder with alifetime prevalence of 2% and mainly characterized by obsessional ideasand compulsive behaviors and rituals. Bilateral stimulation in theanterior limbs of the internal capsules (Nuttin, Cosyns et al., 1999;Nuttin, Gabriels et al., 2003) or nucleus accumbens stimulation (Sturm,Lenartz et al., 2003) can improve symptoms but at high frequency andhigh intensity stimulation. Thus, the present invention can be used toproduce burst mode stimulation to treat an obsessive-compulsivedisorder.

3. Tourette's Syndrome

Tourette syndrome (TS) is a neuropsychiatric disorder with onset inearly childhood. It is characterized by tics and often accompanied bydisturbances in behavior, such as obsessive-compulsive disorder (OCD).Bilateral thalamic stimulation, with promising results on tics andobsessive-compulsive symptoms has been performed as a treatment.(Visser-Vandewalle, Temel et al., 2003; Temel and Visser-Vandewalle2004). Thus, it is envisioned that the stimulation system and/or methodof the present invention can be used to treat TS.

VII. Examples

The following examples are included to demonstrate preferred embodimentsof the invention. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques discovered by the inventors to function well in the practiceof the invention, and thus can be considered to constitute preferredmodes for its practice. However, those of skill in the art should, inlight of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit and scope ofthe invention.

Example Burst Mode Neuromodulation Using TMS

It has been demonstrated that white noise does not react to electricalstimulation of the auditory cortex (De Ridder, De Mulder et al. 2005).Transcranial magnetic stimulation (TMS) is capable of verifying tinnitussuppression in a non-invasive way (Plewnia, Bartels et al. 2003; DeRidder, Verstraeten et al. 2005). However, effects of tonic transcranialmagnetic simulation on synaptic plasticity are often weak, highlyvariable between individuals, and rarely last longer than 30 min. Thetaburst TMS on the other hand produces a controllable, consistent,long-lasting, and powerful effect on motor cortex physiology andbehavior after an application period of only 20-190 s (Huang, Edwards etal. 2005). In other words it is a more powerful way of modifying brainfunctioning.

To demonstrate that the above, 22 patients with unilateral white noiseor narrow band tinnitus were evaluated using both tonic and burst modetranscranial magnetic stimulation (TMS). Tinnitus attenuation wasmeasured using a Visual Analog Scale, and the amount of tinnitussuppression was compared using both stimulation settings.

Three patients were excluded because of a placebo positive result, 10patients did not demonstrate a tinnitus suppression, neither with tonic,nor with burst TMS, so 9 patients were finally included for comparison.

Average tinnitus suppression in these patients was 8.3% for tonic mode,and 54.5% for burst mode, a statistically significant difference(Wilcoxon matched pairs test, Z=2.520504, p=0.012 (0.011719)),demonstrating the clinical superiority of burst mode stimulation fortreating tinnitus.

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All patents and publications mentioned in the specifications areindicative of the levels of those skilled in the art to which theinvention pertains. All patents and publications are herein incorporatedby reference to the same extent as if each individual publication wasspecifically and individually indicated to be incorporated by reference.

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Although the present invention and its advantages have been described indetail, it should be understood that various changes, substitutions andalterations can be made herein without departing from the invention asdefined by the appended claims. Moreover, the scope of the presentapplication is not intended to be limited to the particular embodimentsof the process, machine, manufacture, composition of matter, means,methods and steps described in the specification. As one will readilyappreciate from the disclosure, processes, machines, manufacture,compositions of matter, means, methods, or steps, presently existing orlater to be developed that perform substantially the same function orachieve substantially the same result as the corresponding embodimentsdescribed herein may be utilized. Accordingly, the appended claims areintended to include within their scope such processes, machines,manufacture, compositions of matter, means, methods, or steps.

What is claimed is:
 1. A method of stimulating nerve tissue of a patientusing an implantable pulse generator, the method comprising: generating,by the implantable pulse generator, a burst stimulus that comprises aplurality of groups of spike pulses, wherein the burst stimulus issubstantially quiescent between the plurality of groups, wherein eachspike within each group is separated by a maximum inter-spike intervaland each group of spikes is separated by a minimum inter-group interval,wherein the maximum inter-spike interval is 5 milliseconds and theminimum inter-group interval is 20 milliseconds; providing the burststimulus from the implantable pulse generator to a medical lead; andapplying the burst stimulus to nerve tissue of the patient via one orseveral electrodes of the medical lead.